Cyclohexane derivative and pharmaceutical use thereof

ABSTRACT

A method relieves both nociceptive pain and neuropathic pain and has fewer side effects. The compound includes cyclohexane derivatives represented by the following compound, or pharmaceutically acceptable salts thereof or prodrugs thereof.

RELATED APPLICATIONS

This is divisional application of U.S. application Ser. No. 13/126,901,filed Apr. 29, 2011, which is a §371 of International Application No.PCT/JP2009/068644, with an international filing date of Oct. 30, 2009(WO 2010/050577 A1, published May 6, 2010), which is based on JapanesePatent Application No. 2008-281258, filed Oct. 31, 2008, and JapanesePatent Application No. 2009-176619, filed Jul. 29, 2009, the subjectmatter of which is incorporated by reference.

TECHNICAL FIELD

This disclosure relates to cyclohexane derivatives and their medicaluse.

BACKGROUND

Pain is an experience that is accompanied by an uncomfortable sense oruncomfortable emotion, which occurs when a tissue is damaged or tissuemay be damaged. Pain is roughly divided into nociceptive pain andneuropathic pain depending on its cause.

The term “nociceptive pain” means a pain caused when a tissue of thebody was damaged or a nociceptive stimulus that may cause such damagewas given to a tissue of the body, and a nociceptive pain is causedthrough a nociceptor. Examples of the nociceptive pain includephysiological pains and inflammatory pains.

The term “neuropathic pain” means a pathological pain due to afunctional abnormality of the peripheral nerve or the central nervoussystem itself, and a neuropathic pain is caused by a direct damage to,or pressure on, a nerve without a nociceptive stimulus to a nociceptor.

Examples of therapeutic drugs of nociceptive pain include nonsteroidalanti-inflammatory drugs (NSAIDs) and narcotic analgesics (e.g., opioid),and examples of therapeutic drugs of neuropathic pain includeanticonvulsants, antidepressants, antianxiety agents, and antiepilepticssuch as gabapentin and pregabalin.

Further, in recent years, it has been reported that a pyrazolederivative is effective as an analgesic or a therapeutic drug forneuropathic pain (WO 08/105,383) and that the cyclohexane derivative ofthe following Formula having sulfonyl on an aromatic ring linked to apyrazole ring has an analgesic effect on neuropathic pain (WO00/066562):

However, in terms of cyclohexane derivatives, whether or not compoundshaving no sulfur functional group on the aromatic ring linked to thepyrazole ring have an analgesic action has not been revealed, and thepossibility that such compounds have an analgesic effect has not beensuggested so far.

Further, it is known that administration of a nonsteroidalanti-inflammatory drug is accompanied by side effects such asgastrointestinal dysfunction and renal disorder, and administration of anarcotic analgesic is accompanied by side effects such as constipation,drowsiness, nausea and vomiting. Further, it has been pointed out thatadministration of the above-described therapeutic drugs for neuropathicpain is frequently accompanied by central nervous system side effectssuch as vertigo, nausea and vomiting, and therefore that their long-termadministration is difficult.

Further, since the mechanism by which pain is caused is largelydifferent between nociceptive pain and neuropathic pain, a compoundhaving a strong analgesic effect on both of the pains has not beendeveloped so far.

Thus, it could be helpful to provide a compound having a stronganalgesic effect on both nociceptive pain and neuropathic pain andshowing less side effects, and its medical use.

SUMMARY

We discovered cyclohexane derivatives having a strong analgesic effecton both nociceptive pain and neuropathic pain, which cyclohexanederivatives are excellent in metabolic stability and safety.

That is, we provide a cyclohexane derivative represented by Formula (I):

wherein

A represents a substituent represented by Formula (IIa) or (IIb):

R¹ and R² each independently represent a hydrogen atom, chlorine atom,C₁-C₃ haloalkyl, C₁-C₄ alkyl, C₁-C₄ alkoxy or cyano;

R³ represents a hydrogen atom or chlorine atom;

R⁴ represents a fluorine atom, hydroxymethyl or hydroxyl;

R⁵ and R⁶ each independently represent a hydrogen atom, fluorine atom,C₁-C₃ haloalkyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, alkoxy,hydroxyl or C₂-C₅ alkylcarbonyloxy, or R⁵ and R⁶ may together form anoxo group;

R⁷ and R⁸ each independently represent a hydrogen atom or fluorine atom;

Y represents an oxygen atom or sulfur atom; and

Z represents a nitrogen atom or methane

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Preferably, in the above cyclohexane derivative, R¹ and R² eachindependently represent a hydrogen atom, chlorine atom, C₁-C₃ haloalkyl,C₁-C₄ alkyl or C₁-C₄ alkoxy; R⁵ and R⁶ each independently represent ahydrogen atom, fluorine atom, C₁-C₃ haloalkyl, carboxyl, C₁-C₄ alkoxy,hydroxyl or C₂-C₅ alkylcarbonyloxy, or R⁵ and R⁶ may together form anoxo group; and R⁷ and R⁸ are hydrogen atoms.

More preferably, in the above cyclohexane derivative, R¹ and R² eachindependently represent trifluoromethyl, methyl or methoxy; R³represents a hydrogen atom; R⁴ represents hydroxymethyl or hydroxyl; R⁵and R⁶ each independently represent a hydrogen atom, fluorine atom,trifluoromethyl, carboxyl, methoxy, hydroxyl or acetyloxy (or R⁵ and R⁶may together form an oxo group).

We also provide a pharmaceutical comprising an effective amount of theabove cyclohexane derivative or a pharmaceutically acceptable saltthereof or a prodrug thereof.

The pharmaceutical is preferably an analgesic, more preferably atherapeutic drug for neuropathic pain and/or nociceptive pain. Morepreferably, the above pharmaceutical has a strong analgesic effect alsoon diabetic neuropathic pain and can be suitably used as a therapeuticdrug for diabetic neuropathic pain.

Since the cyclohexane derivative or a pharmaceutically acceptable saltthereof or a prodrug thereof exerts an analgesic effect on nociceptivepain and neuropathic pain as well as diabetic neuropathic pain, atherapeutic effect for pain can be exerted in a patient suffering frompain whose etiology is unknown. Further, the cyclohexane derivative or apharmaceutically acceptable salt thereof or a prodrug thereof has astrong analgesic effect and less side effects, it can be administered asa pharmaceutical for a wide range of pain symptoms including diabeticneuropathic pain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing the effect of the compound of Example 2-A ina mouse partial sciatic nerve ligation model (oral administration).

FIG. 2 is a diagram showing the effect of the compound of Example 2-B ina mouse partial sciatic nerve ligation model (oral administration).

FIG. 3 is a diagram showing the effect of the compound of Example 62 ina mouse partial sciatic nerve ligation model (oral administration).

FIG. 4 is a diagram showing the effect of the compound of ComparativeExample 29 in a mouse partial sciatic nerve ligation model (oraladministration).

FIG. 5 is a diagram showing the effect of the compound of Example 2-B ina mouse model having pain due to streptozotocin (STZ)-induced diabeticneuralgia (oral administration).

FIG. 6 is a diagram showing the change in the plasma level of thecompound of Example 2-B in mice to which the compound of Example 2-B wasadministered.

FIG. 7 is a diagram showing the change in the plasma level of thecompound of Comparative Example 29 in mice to which the compound ofComparative Example 29 was administered.

DETAILED DESCRIPTION

The following terms used in the specification are defined as describedbelow unless otherwise specified.

The cyclohexane derivative is represented by Formula (I):

wherein

A represents a substituent represented by Formula (IIa) or (IIb) below:

R¹ and R² each independently represent a hydrogen atom, chlorine atom,C₁-C₃ haloalkyl, C₁-C₄ alkyl, C₁-C₄ alkoxy or cyano;

R³ represents a hydrogen atom or chlorine atom; R⁴ represents a fluorineatom, hydroxymethyl or hydroxyl;

R⁵ and R⁶ each independently represent a hydrogen atom, fluorine atom,C₁-C₃ haloalkyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, C₁-C₄alkoxy, hydroxyl or C₂-C₅ alkylcarbonyloxy, or R⁵ and R⁶ may togetherform an oxo group;

R⁷ and R⁸ each independently represent a hydrogen atom or fluorine atom;

Y represents an oxygen atom or sulfur atom; and

Z represents a nitrogen atom or methane.

“C₁-C₄ alkyl” means a linear, branched or cyclic alkyl group having 1 to4 carbon atoms, and examples thereof include methyl, ethyl, n-propyl,isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, sec-butyl andtert-butyl.

“C₁-C₄ alkoxy” means a linear, branched or cyclic alkyl-oxy group having1 to 4 carbon atoms, and examples thereof include methoxy, ethoxy,n-propyloxy, isopropyloxy, cyclopropyloxy, n-butoxy, sec-butoxy andtert-butoxy.

“C₁-C₃ haloalkyl” means a linear alkyl group having 1 to 3 carbon atomswherein the hydrogen atoms on the group are partially or entirelysubstituted with a halogen atom(s) (the halogen atom means a fluorineatom, chlorine atom, bromine atom or iodine atom), and examples thereofinclude monochloromethyl, monofluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl and pentafluoroethyl.

Examples of “C₂-C₅ alkylcarbonyloxy” include acetyloxy, ethanoyloxy,propanoyloxy, isopropanoyloxy, butanoyloxy, isobutanoyloxy andpivaloyloxy.

In Formula (I), A preferably represents (IIc).

Y preferably represents a sulfur atom.

R¹ and R² each independently preferably represent a hydrogen atom,chlorine atom, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl,methoxy, ethoxy, n-propyloxy, isopropyloxy or cyano, and more preferablyrepresent trifluoromethyl, methyl or methoxy.

R³ preferably represents a hydrogen atom.

R⁴ preferably represents hydroxyl.

Preferably, R⁵ and R⁶ each independently represent a hydrogen atom,fluorine atom, trifluoromethyl, carboxyl, methoxycarbonyl,ethoxycarbonyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, hydroxyl,acetyloxy, propanoyloxy, butanoyloxy, isobutanoyloxy or pivaloyloxy, orR⁵ and R⁶ together form an oxo group. More preferably, R⁵ and R⁶ eachindependently represent a hydrogen atom, fluorine atom, trifluoromethyl,carboxyl, methoxy, hydroxyl or acetyloxy, or R⁵ and R⁶ together form anoxo group.

R⁷ and R⁸ each independently preferably represent a hydrogen atom orfluorine atom, and more preferably represent a hydrogen atom.

Particular preferred examples of the compounds represented by Formula(I) and pharmaceutically acceptable salts thereof (hereinafter referredto as Compounds (I)) are shown in Table 1, but these do not restrict thescope of the appended claims.

TABLE 1 Com- pound Structural formula  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

In cases where asymmetric carbon atoms exist in Compound (I), all theenantiomers and mixtures thereof are included.

Further, in cases where stereoisomers exist in Compound (I), all thestereoisomers and mixtures thereof are included.

Examples of the “pharmaceutically acceptable salt” include inorganicacid salts such as hydrochloride, sulfate, phosphate and hydrobromide;organic acid salts such as oxalate, malonate, citrate, fumarate,lactiate, malate, succinate, tartarate, acetate, trifluoroacetate,maleate, gluconate, benzoate, ascorbate, methanesulfonate,p-toluenesulfonate and cinnamate; inorganic base salts such as sodiumsalt, potassium salt, calcium salt, magnesium salt and ammonium salt;and organic base salts such as methylamine salt, diethylamine salt,trimethylamine salt, triethylamine salt, pyridinium salt,triethanolamine salt, ethylenediamine salt and guanidium salt. Further,Compound (I) may form a hydrate, solvate or crystalline polymorph.

Compound (I) can be synthesized, for example, according to theproduction method described below. The symbols in each reaction formulahave the same meanings as those defined above unless otherwisespecified.

In cases where the raw material compound has a carboxyl group or ahydroxyl group, a protective group commonly used may be introduced, andthe protective group may be removed as required after the reaction.Examples of the protective group of the hydroxyl group include C₁-C₄alkyl, phenyl, trityl, C₁-C₄ aralkyl (e.g., benzyl), acyl (e.g., formyl,acetyl and benzoyl), C₇-C₁₀ aralkyl-carbonyl (e.g., benzylcarbonyl), andsubstituted silyl (e.g., trimethylsilyl, triethylsilyl andtert-butyldimethylsilyl). Examples of the protective group of thecarboxyl group include C₁-C₄ alkyl.

The method of removal of the protective group varies depending on thetype of the protective group, and the removal can be carried outaccording to a method described in PROTECTIVE GROUPS IN ORGANICSYNTHESIS (WILEY-INTER-SCIENCE) or a method corresponding thereto.

In the production method described below, a salt can be used as the rawmaterial compound. Examples of the salt include those described above aspharmaceutically acceptable salts.

Compound (I) obtained by the production method described below can beisolated and purified according to conventional methods, and examples ofthe methods include solvent extraction, recrystallization andchromatography.

In cases where Compound (I) has optical isomers, stereoisomers, regioisomers and/or rotamers, each of these can be obtained as singlecompounds by a conventional synthesis method and separation method.

Production Method 1: Production Method of Compound (Ic), Compound (Id),Compound (Ie) and Compound (If)

wherein R^(5a) and R^(6a) each independently represent a hydrogen atom,C₁-C₃ haloalkyl, carboxyl or the like; R⁷ and R⁸ each independentlyrepresent C₁-C₄ alkyl or the like; and the other symbols have the samemeanings as those defined above.

Compound (Ic) can be obtained by alkylation of Compound (Ia), andCompound (Id) can be obtained by alkylation of Compound (Ib). Compound(Ie) can be obtained by acylation of Compound (Ia), and Compound (If)can be obtained by acylation of Compound (Ib).

Step 1 and Step 2

The alkylation reaction of Compound (Ia) or Compound (Ib) is generallycarried out by allowing Compound (Ia) or Compound (Ib) to react with ahalogenated alkyl in a solvent in the presence of a base, and thesolvent is appropriately selected such that it does not inhibit thereaction. Examples of the solvent which does not inhibit the reactioninclude ethers such as tetrahydrofuran, 1,4-dioxane and ethylene glycoldimethyl ether; acetone; acetonitrile; and N,N-dimethylformamide; andmixtures thereof may also be used as the solvent.

Examples of the base include alkali metal hydrogen carbonates such assodium hydrogen carbonate and potassium hydrogen carbonate; alkali metalcarbonates such as potassium carbonate and cesium carbonate; amines suchas triethylamine, diisopropylethylamine and pyridine; potassiumtert-butoxide; and sodium hydride.

The amount of the base to be used is preferably 0.5 to 6 moles, morepreferably 0.8 to 3 moles with respect to 1 mole of Compound (Ia) orCompound (Ib).

The amount of the halogenated alkyl to be used is preferably 0.5 to 5moles, more preferably 0.8 to 2 moles with respect to 1 mole of Compound(Ia) or Compound (Ib).

The reaction temperature of the alkylation reaction is preferably −78 to200° C., more preferably −20 to 100° C.

The reaction time of the alkylation reaction varies depending on thereaction conditions, and is preferably 5 minutes to 78 hours, morepreferably 30 minutes to 48 hours.

Step 3 and Step 4

The acylation reaction of Compound (Ia) or Compound (Ib) is generallycarried out by allowing Compound (Ia) or Compound (Ib) to react with anacylating agent such as an acid halide or acid anhydride in a solvent inthe presence of a base, and the solvent is appropriately selected suchthat it does not inhibit the reaction. Examples of the solvent whichdoes not inhibit the reaction include halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; and ethers such as tetrahydrofuran,1,2-dimethoxyethane and 1,4-dioxane; and mixtures thereof may also beused as the solvent.

Examples of the base include pyridine, triethylamine,diisopropylethylamine and N,N-dimethylaminopyridine.

The amount of the acid halide or acid anhydride to be used is preferably0.5 to 3 moles, more preferably 0.8 to 1.5 moles with respect to 1 moleof Compound (Ia) or Compound (Ib).

The amount of the base to be used is preferably 0.1 to 6 moles, morepreferably 0.8 to 3 moles with respect to 1 mole of Compound (Ia) orCompound (Ib).

The reaction temperature of the acylation reaction is preferably −20 to150° C., more preferably 0 to 100° C.

The reaction time of the acylation reaction varies depending on thereaction conditions, and is preferably 5 minutes to 72 hours, morepreferably 30 minutes to 48 hours.

Production Method 2: Production Method of Compound (Ih)

wherein R^(5b) and R^(6b) each independently represent a hydrogen atom,fluorine atom, C₁-C₃ haloalkyl, C₁-C₄ alkoxy, C₂-C₅ alkylcarbonyloxy orthe like; and the other symbols have the same meanings as those definedabove.

Compound (Ih) can be obtained by fluorination of Compound (Ig).

Step 5

The fluorination of Compound (Ig) is generally carried out by allowingCompound (Ig) to react with a fluorinating agent in a solvent, and thesolvent is appropriately selected such that it does not inhibit thereaction. Examples of the solvent which does not inhibit the reactioninclude hydrocarbons such as octane, hexane, benzene and toluene;halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride and 1,2-dichloroethane; ethers such as tetrahydrofuran,1,2-dimethoxyethane and 1,4-dioxane; and alkyl nitriles such asacetonitrile; and mixtures thereof may also be used as the solvent.

Examples of the fluorinating agent include alkylaminosulfur trifluoridessuch as (dimethylamino)sulfur trifluoride (DAST) andbis(2-methoxyethyl)aminosulfur trifluoride acid.

The amount of the fluorinating agent to be used is preferably 0.25 to 20moles, more preferably 0.5 to 4 moles with respect to 1 mole of Compound(Ig).

The reaction temperature of the fluorination reaction is preferably −20to 150° C., more preferably 0 to 100° C.

The reaction time of the fluorination reaction varies depending on thereaction conditions, and is preferably 5 minutes to 72 hours, morepreferably 30 minutes to 48 hours.

Production Method 3: Production Method of Compound (Ij)

wherein the symbols have the same meanings as those defined above.

Compound (Ij) can be obtained by fluorination of Compound (Ii).

Step 6

The fluorination reaction of Compound (Ii) is generally carried out byallowing Compound (Ii) to react with a fluorinating agent in a solvent,and the solvent is appropriately selected such that it does not inhibitthe reaction. Examples of the solvent which does not inhibit thereaction include hydrocarbons such as octane, hexane, benzene andtoluene; halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride and 1,2-dichloroethane; ethers such astetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; and alkyl nitrilessuch as acetonitrile; and mixtures thereof may also be used as thesolvent.

Examples of the fluorinating agent include alkylaminosulfur trifluoridessuch as (dimethylamino)sulfur trifluoride (DAST) andbis(2-methoxyethyl)aminosulfur trifluoride acid.

The amount of the fluorinating agent to be used is preferably 0.25 to 20moles, more preferably 0.5 to 4 moles with respect to 1 mole of Compound(Ii).

The reaction temperature of the fluorination reaction is preferably −20to 150° C., more preferably 0 to 100° C.

The reaction time of the fluorination reaction varies depending on thereaction conditions, and is preferably 5 minutes to 72 hours, morepreferably 30 minutes to 48 hours.

Production Method 4: Production Method of Compound (Ik) and Compound(Il)

wherein the symbols have the same meanings as those defined above.

Compound (Ik) and Compound (Il) can be obtained by reduction of Compound(Ii).

Step 7

The reduction reaction of Compound (Ii) is generally carried out byallowing Compound (Ii) to react with a reducing agent in a solvent, andthe solvent is appropriately selected such that it does not inhibit thereaction. Examples of the solvent which does not inhibit the reactioninclude hydrocarbons such as octane, hexane, benzene and toluene; etherssuch as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether anddiethyl ether; and alcohols such as methanol, ethanol and isopropylalcohol; and mixtures thereof may also be used as the solvent.

Examples of the reducing agent include sodium borohydride, lithiumborohydride, diisobutylaluminum hydride, lithium aluminum hydride,lithium triethyl hydride, sodium bis(2-methoxyethoxy)aluminum hydrideand borane complexes.

The amount of the reducing agent to be used is preferably 0.25 to 100moles, more preferably 0.5 to 20 moles with respect to 1 mole ofCompound R.

The reaction temperature of the reduction reaction is preferably −78 to150° C., more preferably −78 to 100° C.

The reaction time of the reduction reaction varies depending on thereaction conditions such as the reaction temperature and the amount ofthe reducing agent, and is preferably 5 minutes to 72 hours, morepreferably 30 minutes to 24 hours.

Production Method 5: Production Method of Compound (Im) and Compound(In)

wherein the symbols have the same meanings as those defined above.

Compound (Im) and Compound (In) are obtained by trifluoromethylation ofCompound (Ii).

Step 8

Examples of the trifluoromethylating reagent include organosiliconcompounds such as (trifluoromethyl)trimethylsilane. Thetrifluoromethylation reaction using an organosilicon compound can becarried out by the method described in Journal of the American ChemicalSociety, 1989, Vol. 39, p. 393-395 or a method corresponding thereto.

Production Method 6: Production Method of Compound (Io)

wherein the symbols have the same meanings as those defined above.

Compound (SI) is obtained by allowing a Wittig reagent (LI) to act onCompound (Ii), followed by hydrolyzing the resulting compound. TheWittig reagent (LI) employed may be one commercially available, but thereagent may also be synthesized according to a known method. Compound(Io) is obtained by oxidizing Compound (SI).

Step 9

The Wittig reaction of Compound (Ii) is generally carried out byallowing Compound (Ii) to react with a Wittig reagent in a solvent inthe presence of a base, and the solvent is appropriately selected suchthat it does not inhibit the reaction. Examples of the solvent whichdoes not inhibit the reaction include hydrocarbons such as octane,hexane, benzene and toluene; and ethers such as tetrahydrofuran,1,4-dioxane, ethylene glycol dimethyl ether and diethyl ether; andmixtures thereof may also be used as the solvent.

Examples of the base include lithium diisopropylamide, potassiumtert-butoxide, sodium hydride, phenyllithium and tert-butyllithium.

The amount of the base to be used is preferably 0.5 to 3 moles, morepreferably 0.8 to 2 moles with respect to 1 mole of Compound (Ii).

The amount of Compound (LI) to be used is preferably 0.5 to 3 moles,more preferably 0.8 to 2 moles with respect to 1 mole of Compound (Ii).

The reaction temperature of the Wittig reaction is preferably −78 to100° C., more preferably −78 to 50° C.

The reaction time of the Wittig reaction varies depending on thereaction conditions, and is preferably 5 minutes to 48 hours, morepreferably 30 minutes to 24 hours.

The hydrolysis reaction to obtain Compound (SI) is carried out in asolvent appropriately selected, which solvent does not inhibit thereaction. Examples of the solvent which does not inhibit the reactioninclude ethers such as tetrahydrofuran, 1,4-dioxane and ethylene glycoldimethyl ether; alcohols such as methanol, ethanol and tert-butanol;acetonitrile; and water; and mixtures thereof may also be used as thesolvent.

The concentration of the acid used in the hydrolysis reaction ispreferably 0.1 to 12 M, and the amount of the acid to be used ispreferably 1 mole to an excess amount with respect to 1 mole of Compound(Ii).

Examples of the acid to be used in the hydrolysis reaction includeinorganic acids such as hydrochloric acid and sulfuric acid; and organicacids such as acetic acid.

The reaction temperature of the hydrolysis reaction is preferably −20 to200° C., more preferably 0 to 100° C.

The reaction time of the hydrolysis reaction varies depending on thereaction conditions, and is preferably 5 minutes to 48 hours, morepreferably 30 minutes to 24 hours.

Step 10

Examples of the oxidizing agent to be used in the oxidation reaction ofCompound (SI) include chromium oxide (VI)-acetic acid, Jones reagent andsodium chlorite. The oxidation reaction may be carried out according toa known method.

Production Method 7: Production Method of Compound (Ii)

wherein R⁹ and R¹⁰ each independently represent methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, tert-butyl or the like, or R⁹ and R¹⁰ maytogether form an ethylene group (—CH₂CH₂—) or a propylene group(—CH₂CH₂CH₂—); and the other symbols have the same meanings as thosedefined above.

Compound (Ii) is obtained by deprotection of Compound (Ip).

Step 11

The deprotection reaction of Compound (Ip) may be carried out accordingto a method described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS(WILEY-INTERSCIENCE) or a method corresponding thereto.

Production Method 8: Production Method of Compound (IIIb)

wherein the symbols have the same meanings as those defined above.

Compound (IIIb) can be obtained by chlorination of Compound (IIIa).

Step 12

The chlorination reaction of Compound (IIIa) is generally carried out byallowing Compound (IIIa) to react with a chlorinating agent in asolvent, and the solvent is appropriately selected such that it does notinhibit the reaction. Examples of the solvent which does not inhibit thereaction include halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride and 1,2-dichloroethane; acetonitrile;and ethyl acetate; and mixtures thereof may also be used as the solvent.

Examples of the chlorinating agent include N-chlorosuccinimide (NCS).

The amount of the chlorinating agent to be used is preferably 0.5 to 2moles, more preferably 0.8 to 1.2 moles with respect to 1 mole ofCompound (IIIa).

The reaction temperature of the chlorination reaction is preferably 0 to200° C., more preferably 0 to 120° C.

The reaction time of the chlorination reaction varies depending on thereaction conditions such as the reaction temperature, and is preferably5 minutes to 72 hours, more preferably 30 minutes to 48 hours.

Production Method 9: Production Method of Compound (IIIa)

wherein the symbols have the same meanings as those defined above.

Compound (IIIa) can be obtained by cyclization of Compound (LII) andCompound (SII). The Compound (LII) may be one commercially available,but it may also be synthesized according to a known method.

Step 13

The cyclization reaction of Compound (LII) and Compound (SIT) isgenerally carried out in a solvent appropriately selected such that itdoes not inhibit the reaction. Examples of the solvent which does notinhibit the reaction include alcohols such as methanol, ethanol andisopropyl alcohol; halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers such astetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; benzene; toluene;acetic acid; and water; and mixtures thereof may also be used as thesolvent.

The amount of Compound (LII) to be used is preferably 0.5 to 1.5 moles,more preferably 0.8 to 1.2 moles with respect to 1 mole of Compound(SII).

In the cyclization reaction, a catalyst may be used, and examples of thecatalyst include organic bases such as triethylamine and pyridine;inorganic acids such as hydrochloric acid and sulfuric acid; and organicacids such as acetic acid.

The amount of the catalyst to be used is preferably 0.1 to 3 moles withrespect to 1 mole of Compound (SII).

The reaction temperature of the cyclization reaction is preferably 0 to200° C., more preferably 0 to 120° C.

The reaction time of the cyclization reaction varies depending on thereaction conditions such as the reaction temperature, and is preferably5 minutes to 72 hours, more preferably 30 minutes to 48 hours.

Production Method 10: Production Method of Compound (IV)

wherein the symbols have the same meanings as those defined above.

Compound (IV) can be obtained by deprotonation and oxidation of Compound(SIII). The oxidation reaction may be carried out according to a methoddescribed in Tetrahedron, 1989, vol. 45, p. 5703-5742 or a methodcorresponding thereto.

Step 14

The deprotonation reaction and the oxidation reaction are generallycarried out by allowing Compound (SIII) to react with a base and anoxidizing agent in an anhydrous solvent, and the solvent isappropriately selected such that it does not inhibit the reaction.Examples of the solvent which does not inhibit the reaction includehydrocarbons such as octane, hexane and heptane; and ethers such astetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether and diethylether; and mixtures thereof may also be used as the solvent.

Examples of the base include butyllithiums such as n-butyllithium,sec-butyllithium and tert-butyllithium.

The amount of the base to be used is preferably 0.8 to 5 moles, morepreferably 0.9 to 3 moles with respect to 1 mole of Compound (SIII).

The amount of Compound (LIII) to be used is preferably 0.8 to 5 moles,more preferably 0.9 to 3 moles with respect to 1 mole of Compound(SIII).

Examples of the oxidizing agent used in the hydrolysis reaction include3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine.

The reaction temperature of the deprotonation reaction and the oxidationreaction is preferably −78 to 150° C., more preferably 0 to 50° C.

The reaction time of the deprotonation reaction and the oxidationreaction varies depending on the reaction conditions, and is preferably5 minutes to 72 hours, more preferably 30 minutes to 48 hours.

Production Method 11: Production Method of Intermediate Compound (VI)

wherein the symbols have the same meanings as those defined above.

Compound (VI) can be obtained by allowing Compound (LIV) to react withCompound (LV) followed by solvolysis of the resulting Compound (V). TheCompound (LIV) and Compound (LV) may be those commercially available,but these may also be synthesized according to known methods.

Step 15

The reaction of Compound (LIV) with Compound (LV) is generally carriedout in an anhydrous solvent in the presence of a base, and the solventis appropriately selected such that it does not inhibit the reaction.Examples of the solvent which does not inhibit the reaction includehydrocarbons such as octane, hexane, benzene and toluene; and etherssuch as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether anddiethyl ether; and mixtures thereof may also be used as the solvent.

Examples of the base include alkyllithiums such as methyllithium andn-butyllithium; and salts of dialkylamines such as lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide and potassiumbis(trimethylsilyl)amide.

The amount of the base to be used is preferably 0.8 to 5 moles, morepreferably 0.9 to 3 moles with respect to 1 mole of Compound (LIV).

The amount of Compound (LV) to be used is preferably 0.8 to 5 moles,more preferably 0.9 to 3 moles with respect to 1 mole of Compound (LIV).

The reaction temperature of the reaction between the Compound (LIV) andCompound (LV) is preferably −78 to 150° C., more preferably −78 to 100°C.

The reaction time of the reaction between the Compound (LIV) andCompound (LV) varies depending on the reaction conditions, and ispreferably 5 minutes to 72 hours, more preferably 30 minutes to 48hours.

Step 16

The solvolysis reaction is generally carried out in a solvent in thepresence of a base, and the solvent is appropriately selected such thatit does not inhibit the reaction. Examples of the solvent which does notinhibit the reaction include alcohols such as methanol and ethanol; andwater; and mixtures thereof may also be used as the solvent.

Examples of the base include potassium carbonate, sodium carbonate,potassium hydroxide and sodium hydroxide.

The amount of the base to be used is preferably 0.5 to 10 moles, morepreferably 0.8 to 3 moles with respect to 1 mole of Compound (V).

The reaction temperature of the solvolysis reaction is preferably −20 to150° C., more preferably 0 to 100° C.

The reaction time of the solvolysis reaction varies depending on thereaction conditions, and is preferably 5 minutes to 72 hours, morepreferably 30 minutes to 48 hours.

Production Method 12: Production Method of Intermediate Compound (SIIa)

wherein R¹¹ represents a chlorine atom; imidazolyl group;N-methoxy-N-methylamino group; or an alkoxy group such as a methoxygroup or ethoxy group; and the other symbols have the same meanings asthose defined above.

Compound (SIIa) can be obtained by allowing Compound (VI) to react withCompound (LVI), followed by oxidizing the resulting Compound (VII).Compound (SIIa) can be obtained also by allowing Compound (VI) to reactwith Compound (LVII). The Compound (LVI) and Compound (LVII) may bethose commercially available, but these may also be synthesizedaccording to known methods.

Step 17 or Step 18

The reaction of Compound (VI) with Compound (LVI) or with Compound(LVII) is generally carried out in an anhydrous solvent in the presenceof a base, and the solvent is appropriately selected such that it doesnot inhibit the reaction. Examples of the solvent which does not inhibitthe reaction include hydrocarbons such as octane, hexane, benzene andtoluene; and ethers such as tetrahydrofuran, 1,4-dioxane, ethyleneglycol dimethyl ether and diethyl ether; and mixtures thereof may alsobe used as the solvent.

Examples of the base include alkyllithiums such as methyllithium andn-butyllithium; and salts of dialkylamines such as lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide and potassiumbis(trimethylsilyl)amide.

The amount of the base to be used is preferably 0.8 to 5 moles, morepreferably 0.9 to 3 moles with respect to 1 mole of Compound (VI).

The amount of Compound (LVI) or Compound (LVII) to be used is preferably0.8 to 5 moles, more preferably 0.9 to 3 moles with respect to 1 mole ofCompound (VI).

The reaction temperature of the reaction of Compound (VI) with Compound(LVI) or with Compound (LVII) is preferably −78 to 150° C., morepreferably 0 to 50° C.

The reaction time of the reaction of Compound (VI) with Compound (LVI)or with Compound (LVII) varies depending on the reaction conditions, andis preferably 5 minutes to 72 hours, more preferably 30 minutes to 48hours.

Step 19

The oxidation reaction of Compound (VII) is generally carried out byallowing Compound (VII) to react with an oxidizing agent in a solvent,and the solvent is appropriately selected such that it does not inhibitthe reaction. Examples of the solvent which does not inhibit thereaction include hydrocarbons such as octane, hexane, benzene andtoluene; halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride and 1,2-dichloroethane; ethers such astetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; alkyl nitrilessuch as acetonitrile; trifluoroacetic acid; pyridine; and acetone; andmixtures thereof may also be used as the solvent.

Examples of the oxidizing agent include commercially available reagentssuch as manganese dioxide; sulfur trioxide-pyridine; activated dimethylsulfoxide; and Dess-Martin reagent.

The amount of the oxidizing agent to be used is preferably 0.5 to 3moles, more preferably 0.8 to 2 moles with respect to 1 mole of Compound(VII).

The reaction temperature of the oxidation reaction varies depending onthe type of the oxidizing agent, and is preferably −78 to 100° C., morepreferably −78 to 40° C.

The reaction time of the oxidation reaction varies depending on thereaction conditions such as the type of the oxidizing agent and thereaction temperature, and is preferably 5 minutes to 72 hours, morepreferably 1 to 24 hours.

Production Method 13: Production Method of Intermediate Compound (IX)

wherein X¹ represents a halogen atom; PG represents a protective groupsuch as methyl or benzyl; R¹² represents an alkoxy group such as methoxyor ethoxy; and the other symbols have the same meanings as those definedabove.

Compound (IX) can be obtained by allowing Compound (VIII) to react withCompound (LVIII). The Compound (VIII) and Compound (LVIII) may be thosecommercially available, but these may also be synthesized according toknown methods.

Step 20

The reaction of Compound (VIII) with Compound (LVIII) is generallycarried out in an anhydrous solvent in the presence of a base, and thesolvent is appropriately selected such that it does not inhibit thereaction. Examples of the solvent which does not inhibit the reactioninclude hydrocarbons such as octane, hexane, benzene and toluene; andethers such as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethylether and diethyl ether; and mixtures thereof may also be used as thesolvent.

Examples of the base include lithium diisopropylamide, lithiumbis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide.

The amount of the base to be used is preferably 0.8 to 4 moles, morepreferably 0.9 to 3.5 moles with respect to 1 mole of Compound (VIII).

The amount of Compound (LVIII) to be used is preferably 0.8 to 5 moles,more preferably 0.9 to 3 moles with respect to 1 mole of Compound(VIII).

The reaction temperature of the reaction of Compound (VIII) withCompound (LVIII) is preferably −78 to 150° C., more preferably 0 to 50°C.

The reaction time of the reaction of Compound (VIII) with Compound(LVIII) varies depending on the reaction conditions, and is preferably 5minutes to 72 hours, more preferably 30 minutes to 48 hours.

Production Method 14: Production Method of Intermediate Compound (XI)

wherein the symbols have the same meanings as those defined above.

Compound (XI) can be obtained by reducing Compound (IX), followed byoxidizing the resulting Compound (X).

Step 21

The reduction reaction of Compound (IX) is generally carried out byallowing Compound (IX) to react with a reducing agent in a solvent, andthe solvent is appropriately selected such that it does not inhibit thereaction. Examples of the solvent which does not inhibit the reactioninclude hydrocarbons such as octane, hexane, benzene and toluene; etherssuch as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether anddiethyl ether; and alcohols such as methanol, ethanol and isopropylalcohol; and mixtures thereof may also be used as the solvent.

Examples of the reducing agent include lithium borohydride,diisobutylaluminum hydride, lithium aluminum hydride, lithium triethylhydride, sodium bis(2-methoxyethoxy)aluminum hydride and boranecomplexes.

The amount of the reducing agent to be used is preferably 0.25 to 100moles, more preferably 0.5 to 20 moles with respect to 1 mole ofCompound (IX).

The reaction temperature of the reduction reaction is preferably −78 to150° C., more preferably −78 to 100° C.

The reaction time of the reduction reaction varies depending on thereaction conditions such as the reaction temperature and the amount ofthe reducing agent, and is preferably 5 minutes to 72 hours, morepreferably 30 minutes to 24 hours.

Step 22

The oxidation reaction of Compound (X) is generally carried by allowingCompound (X) to react with an oxidizing agent in a solvent, and thesolvent is appropriately selected such that it does not inhibit thereaction. Examples of the solvent which does not inhibit the reactioninclude trifluoroacetic acid, pyridine, acetone, hydrocarbons such asoctane, hexane, benzene and toluene; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ethers such as tetrahydrofuran, 1,2-dimethoxyethaneand 1,4-dioxane; and alkyl nitriles such as acetonitrile; and mixturesthereof may also be used as the solvent.

Examples of the oxidizing agent include commercially available reagentssuch as sulfur trioxide-pyridine; activated dimethyl sulfoxide; andDess-Martin reagent.

The amount of the oxidizing agent to be used is preferably 0.5 to 3moles, more preferably 0.8 to 2 moles with respect to 1 mole of Compound(X).

The reaction temperature of the oxidation reaction varies depending onthe type of the oxidizing agent, and is preferably −78 to 100° C., morepreferably −78 to 40° C.

The reaction time of the oxidation reaction varies depending on thereaction conditions such as the type of the oxidizing agent and thereaction temperature, and is preferably minutes to 72 hours, morepreferably 1 to 24 hours.

Production Method 15: Production Method of Intermediate Compound (XII)

wherein the symbols have the same meanings as those defined above.

Step 23

Compound (XII) can be obtained by converting Compound (XI) to an alkyne.Examples of the reagent to be used in the conversion reaction includedimethyl-1-diazo-2-oxopropylphosphonate. The conversion reaction can becarried out according to the method described in Tetrahedron Letters,2006, vol. 47, pp. 1729-1731 or a method corresponding thereto.

Production Method 16: Production Method of Intermediate Compound (SIIb)

wherein the symbols have the same meanings as those defined above.

Compound (SIIb) can be obtained by allowing Compound (XII) to react withCompound (LVI), followed by oxidizing the resulting Compound (XIII).Compound (SIIb) can be obtained also by allowing Compound (XII) to reactwith Compound (LVII). The Compound (LVI) and Compound (LVII) may bethose commercially available, but these may also be synthesizedaccording to known methods.

Step 24 or Step 25

The nucleophilic addition reaction of Compound (XII) is generallycarried out in an anhydrous solvent in the presence of a base, and thesolvent is appropriately selected such that it does not inhibit thereaction. Examples of the solvent which does not inhibit the reactioninclude hydrocarbons such as octane, hexane, benzene and toluene; andethers such as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethylether and diethyl ether; and mixtures thereof may also be used as thesolvent.

Examples of the base include alkyllithiums such as methyllithium andn-butyllithium; and salts of dialkylamines such as lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide and potassiumbis(trimethylsilyl)amide.

The amount of the base to be used is preferably 0.8 to 5 moles, morepreferably 0.9 to 3 moles with respect to 1 mole of Compound (XII).

The amount of Compound (LVI) or Compound (LVII) to be used is preferably0.8 to 5 moles, more preferably 0.9 to 3 moles with respect to 1 mole ofCompound (XII).

The reaction temperature of the nucleophilic addition reaction ispreferably −78 to 150° C., more preferably 0 to 50° C.

The reaction time of the nucleophilic addition reaction varies dependingon the reaction conditions, and is preferably 5 minutes to 72 hours,more preferably 30 minutes to 48 hours.

Step 26

The oxidation reaction of Compound (XIII) is generally carried out byallowing Compound (XIII) to react with an oxidizing agent in a solvent,and the solvent is appropriately selected such that it does not inhibitthe reaction. Examples of the solvent which does not inhibit thereaction include trifluoroacetic acid, pyridine, acetone, hydrocarbonssuch as octane, hexane, benzene and toluene; halogenated hydrocarbonssuch as dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ethers such as tetrahydrofuran, 1,2-dimethoxyethaneand 1,4-dioxane; and alkyl nitriles such as acetonitrile; and mixturesthereof may also be used as the solvent.

Examples of the oxidizing agent include commercially available reagentssuch as manganese dioxide; sulfur trioxide-pyridine; activated dimethylsulfoxide; and Dess-Martin reagent.

The amount of the oxidizing agent to be used is preferably 0.5 to 3moles, more preferably 0.8 to 2 moles with respect to 1 mole of Compound(XIII).

The reaction temperature of the oxidation reaction varies depending onthe type of the oxidizing agent, and is preferably −78 to 100° C., morepreferably −78 to 40° C.

The reaction time of the oxidation reaction varies depending on thereaction conditions such as the type of the oxidizing agent and thereaction temperature, and is preferably 5 minutes to 72 hours, morepreferably 1 to 24 hours.

Production Method 17: Production Method of Intermediate Compound (SIIIa)

wherein the symbols have the same meanings as those defined above.

Compound (SIIIa) can be obtained by alkylating Compound (XIV) withCompound (LX) or acylating Compound (XVI) obtained from Compound (XIV)with Compound (LXI), thereby obtaining Compound (XV), which is thencyclized. Compound (XIV) and Compound (LX) can be synthesized accordingto known methods. The Compound (LXI) may be one commercially available,but it may also be synthesized according to a known method.

Step 27

The alkylation reaction of Compound (XIV) is generally carried out byallowing Compound (XIV) to react with a halogenated alkyl in a solventin the presence of a base, and the solvent is appropriately selectedsuch that it does not inhibit the reaction. Examples of the solventwhich does not inhibit the reaction include ethers such astetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether;acetone; acetonitrile; and N,N-dimethylformamide; and mixtures thereofmay also be used as the solvent.

Examples of the base include alkali metal hydrogen carbonates such assodium hydrogen carbonate and potassium hydrogen carbonate; alkali metalcarbonates such as potassium carbonate and cesium carbonate; amines suchas triethylamine, diisopropylethylamine and pyridine; potassiumtert-butoxide; and sodium hydride.

The amount of the base to be used is preferably 0.5 to 6 moles, morepreferably 0.8 to 3 moles with respect to 1 mole of Compound (XIV).

The amount of the Compound (LX) to be used is preferably 0.5 to 5 moles,more preferably 0.8 to 2 moles with respect to 1 mole of Compound (XIV).

The reaction temperature of the alkylation reaction is preferably −78 to200° C., more preferably −20 to 100° C.

The reaction time of the alkylation reaction varies depending on thereaction conditions, and is preferably 5 minutes to 78 hours, morepreferably 30 minutes to 48 hours.

Step 28

Compound (XVI) can be synthesized from Compound (XIV) according to, forexample, a method using thionyl chloride, oxalyl chloride or the like,which known method.

Step 29

The acylation reaction of Compound (LXI) with Compound (XVI) isgenerally carried out in a solvent in the presence of a base, and thesolvent is appropriately selected such that it does not inhibit thereaction. Examples of the solvent which does not inhibit the reactioninclude halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride and 1,2-dichloroethane; and ethers such astetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; and mixturesthereof may also be used as the solvent.

Examples of the base include pyridine, triethylamine,diisopropylethylamine and N,N-dimethylaminopyridine.

The amount of the base to be used is preferably 0.1 to 6 moles, morepreferably 0.8 to 3 moles with respect to 1 mole of Compound (XVI).

The amount of Compound (LXI) to be used is 0.5 to 3 moles, morepreferably 0.8 to 1.5 moles with respect to 1 mole of Compound (XVI).

The reaction temperature of the acylation reaction is preferably −20 to150° C., more preferably 0 to 100° C.

The reaction time of the acylation reaction varies depending on thereaction conditions, and is preferably 5 minutes to 72 hours, morepreferably 30 minutes to 48 hours.

Step 30

The cyclization reaction of Compound (XV) is generally carried out in asolvent in the presence of an ammonium salt, and the solvent is selectedsuch that it does not inhibit the reaction. Examples of the solventwhich does not inhibit the reaction include acetic acid and formic acid;and mixtures thereof may also be used as the solvent.

Examples of the ammonium salt include ammonium acetate, ammonium formateand ammonium carbonate, which are commercially available reagents.

The amount of the ammonium salt to be used is preferably 1 to 20 moles,more preferably 2 to 15 moles with respect to 1 mole of Compound (XV).

The reaction temperature of the cyclization reaction is preferably 0 to200° C., more preferably 0 to 120° C.

The reaction time of the cyclization reaction varies depending on thereaction conditions, and is preferably 5 minutes to 100 hours, morepreferably 30 minutes to 48 hours.

Production Method 18: Production Method of Intermediate Compound (SIIIb)

wherein the symbols have the same meanings as those defined above.

Compound (SIIIb) can be obtained by amidating Compound (XIV) and thenthioamidating the resulting Compound (XVII) to produce Compound (XVIII),which is then cyclized using Compound (LX). Compound (XIV) can besynthesized according to a known method. Compound (LX) can also besynthesized according to a known method.

Step 31

The amidation reaction of Compound (XIV) is generally carried out byforming a mixed anhydride in a solvent in the presence of a base using achloroformic ester or the like, followed by allowing aqueous ammonia toreact with the mixed anhydride. The solvent is appropriately selectedsuch that it does not inhibit the reaction. Examples of the solventwhich does not inhibit the reaction include ethers such astetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether;halogenated hydrocarbons such as dichloromethane and chloroform; andN,N-dimethylformamide; and mixtures thereof may also be used as thesolvent.

Examples of the chloroformic ester include methyl chloroformate, ethylchloroformate, isopropyl chloroformate and sec-butyl chloroformate.

The amount of the chloroformic ester is preferably 0.5 to 4 moles, morepreferably 0.9 to 2 moles with respect to 1 mole of Compound (XIV).

Examples of the base include inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate and cesium carbonate;and organic bases such as triethylamine, diisopropylethylamine andpyridine.

The amount of the base to be used is preferably 0.5 to 5 moles, morepreferably 0.9 to 2.5 moles with respect to 1 mole of Compound (XIV).

The reaction temperature of the amidation reaction is preferably −78 to200° C., more preferably −20 to 100° C. in terms of the formation of amixed anhydride. In terms of the reaction after addition aqueousammonia, the temperature is preferably −78 to 200° C., more preferably−20 to 100° C.

The reaction time of the amidation reaction varies depending on thereaction conditions, and is preferably 5 minutes to 48 hours, morepreferably 30 minutes to 24 hours in terms of the formation of a mixedanhydride. In terms of the reaction after addition aqueous ammonia, thereaction time is preferably 5 minutes to 72 hours, more preferably 30minutes to 48 hours

Step 32

The thioamidation reaction of Compound (XVII) is generally carried outby allowing Compound (XVII) to react with Lawesson's reagent orphosphorus pentasulfide, which are commercially available reagents, in asolvent. The solvent is appropriately selected such that it does notinhibit the reaction. Examples of the solvent which does not inhibit thereaction include saturated hydrocarbons such as benzene and toluene;halogenated solvents such as dichloromethane and chloroform; and etherssuch as tetrahydrofuran and 1,4-dioxane; and mixtures thereof may alsobe used as the solvent.

The amount of the Lawesson's reagent or phosphorus pentasulfide to beused is preferably 0.3 to 4 moles, more preferably 0.4 to 2 moles withrespect to 1 mole of Compound (XVII).

The reaction temperature of the thioamidation reaction is preferably −20to 200° C., more preferably 0 to 120° C.

The reaction time of the thioamidation reaction varies depending on thereaction conditions, and is preferably 5 minutes to 72 hours, morepreferably 30 minutes to 48 hours.

Step 33

The cyclization reaction of Compound (XVIII) is generally carried out ina solvent appropriately selected such that it does not inhibit thereaction. Examples of the solvent which does not inhibit the reactioninclude alcohols such as methanol and ethanol; ethers such astetrahydrofuran and 1,4-dioxane; and acetonitrile; and mixtures thereofmay also be used as the solvent.

The amount of Compound (LX) to be used is preferably 0.5 to 4 moles,more preferably 0.9 to 1.5 moles with respect to 1 mole of Compound(XVIII).

The reaction temperature of the cyclization reaction is preferably −20to 200° C., more preferably 0 to 100° C.

The reaction time of the cyclization reaction varies depending on thereaction conditions, and is preferably 5 minutes to 72 hours, morepreferably 30 minutes to 48 hours.

In cases where Compound (I) was obtained as a free form, it may beconverted to a desired salt according to a known method or a methodcorresponding thereto. Conversely, in cases where it was obtained as asalt, it may be converted to a free form or another desired saltaccording to a known method or a method corresponding thereto.

Compound (I) may also be used as a prodrug, and examples of the prodrugof Compound (I) include compounds which are converted to Compound (I) byreaction by an enzyme, gastric acid or the like under physiologicalconditions in a living body, that is, compounds that undergo enzymaticoxidation, reduction or hydrolysis to change into Compound (I); andcompounds that undergo hydrolysis by gastric acid or the like to changeinto Compound (I), which compounds correspond to those wherein ahydroxyl group of Compound (I) was acylated, alkylated, phosphorylatedor borated. Preferred particular examples of the prodrug in cases whereR⁵ or R⁶ of Compound (I) is a hydroxyl group are shown in Table 2, butthese examples do not restrict the scope of this disclosure.

TABLE 2 Compound Structural formula P1

P2

P3

P4

P5

P6

P7

P8

P9

P10

P11

P12

The prodrug of Compound (I) can be synthesized according to a knownmethod from Compound (I). Further, the prodrug of Compound (I) may beone that changes into Compound (I) under the physiological conditionsdescribed in a known document (‘Iyakuhin no Kaihatsu’ (Development ofDrugs), Hirokawa Shoten, 1990, vol. 7, pp. 163-198; Prog. Med. 5, 1985,pp. 2157-2161). By using Compound (I) as a prodrug, its solubilityand/or absorbability may be improved.

The excellent analgesic effect, or therapeutic effect on neuropathicpain or therapeutic action against diabetic neuropathic pain, ofCompound (I) can be evaluated using an appropriate animal model.Examples of the appropriate animal model for nociceptive pain includemouse acetic acid writhing model, rat or mouse formalin test, ratcarrageenin-induced inflammation model, rat hot plate test, andtail-flick test for acute pain.

Examples of the appropriate animal models for neuropathic pain includemouse or rat partial sciatic nerve ligation model and mouse or ratspinal nerve ligation model, and examples of the appropriate animalmodel for diabetic neuropathic pain include mouse or rat streptozotocin(STZ)-induced diabetic neuropathy model.

Since Compound (I) has an excellent analgesic effect, or therapeuticeffect on neuropathic pain or therapeutic effect on diabetic neuropathicpain, the compound can be used as a pharmaceutical, and is preferablyused as an analgesic, therapeutic drug for neuropathic pain, ortherapeutic drug for diabetic neuropathic pain.

In cases where Compound (I) is used as an analgesic, it is preferablyused for nociceptive pain. Examples of the nociceptive pain hereininclude pain due to injuries such as fracture and incised wound;postoperative pain; sprain pain; bruise pain; joint pain; low back pain;muscle pain; pain after tooth extraction; dental pain; appendicitis;chronic rheumatoid arthritis; rheumatic fever; osteoarthritis;ankylosing spondylitis; spondylosis deformans; cervicobrachial syndrome;periarthritis; cellulitis; acute otitis media; prostatitis; alveolarperiostitis; and pain due to inflammatory diseases such as vaginitis.Further, the above-described nociceptive pain include deep pain andvisceral pain (e.g., headache; abdominal pain; back pain; chronic pelvicpain syndrome; pain due to endometriosis; pain due to urolithiasis orurethral calculus; colicky pain due to digestive organ disease, pelvicpain; and urologic diseases pain). In cases where Compound (I) is usedas an analgesic, examples of more preferred target diseases includechronic rheumatoid arthritis, osteoarthritis, postoperative pain, jointpain, low back pain, muscle pain and dental pain.

Compound (I) is used as a therapeutic drug for neuropathic pain, andalso as a therapeutic drug for diabetic neuropathic pain. Examples ofthe neuropathic pain herein include cancer pain, herpes zoster pain,postherpetic neuralgia, AIDS-related neuralgia and trigeminal neuralgia.The diabetic neuropathic pain herein means pain due to diabeticneuralgia.

Compound (I) is also useful for therapy of acute and chronic pain. Acutepain usually continues for a short period of time, and examples thereofinclude postoperative pain, pain after tooth extraction and trigeminalneuralgia. Chronic pain is defined as pain that usually continues for 3to 6 months. It includes somatogenic pain and psychogenic pain, andexamples thereof include chronic rheumatoid arthritis, osteoarthritisand postherpetic neuralgia.

A pharmaceutical containing Compound (I) shows an excellent analgesiceffect, or therapeutic effect on neuropathic pain or diabeticneuropathic pain, in cases where it was administered to a mammal (e.g.,mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey or human),especially human.

Further, Compound (I) may be used not only as an analgesic or atherapeutic drug for neuropathic pain, but also in a therapeutic methodfor pain or neuropathic pain, or in a therapeutic use for pain orneuropathic pain. Further, Compound (I) may be used in a therapeuticmethod or therapeutic use for diabetic neuropathic pain.

The dosage form of Compound (I) may be oral or parenteral administrationof Compound (I) as it is or after blending of a pharmaceuticallyacceptable carrier thereto.

Examples of the dosage form of the drug product containing Compound (I)in cases where it is orally administered include tablets (e.g.,sugar-coated tablets and film-coated tablets), pills, granules, powders,capsules (e.g., soft capsules and microcapsules), syrups, emulsions andsuspensions; examples of the dosage form in cases where it isparenterally administered include injections, impregnating agents, dropsand suppositories. It is also effective to formulate the drug into asustained-release preparation by combining the drug with an appropriatebase (e.g., polymer of butyric acid, polymer of glycolic acid, copolymerof butyric acid-glycolic acid, mixture of a polymer of butyric acid anda polymer of glycolic acid, or polyglycerol fatty acid ester).

Preparation of the drug product containing Compound (I) into theabove-described dosage form can be carried out according to a knownmethod commonly used in the field of drug formulation. In such a case,the formulation can be produced by inclusion of an excipient, binder,lubricant, disintegrant, sweetener, surfactant, suspending agent,emulsifier and/or the like, which are commonly used in the field of drugformulation.

Preparation of a tablet containing Compound (I) may be carried out byinclusion of an excipient, binder, disintegrant, lubricant and/or thelike; and preparation of a pill or granule may be carried out byinclusion of an excipient, binder, disintegrant and/or the like.Preparation of a powder or capsule may be carried out by inclusion of anexcipient and/or the like; preparation of a syrup may be carried out byinclusion of a sweetener and/or the like; and preparation of an emulsionor suspension be carried out by inclusion of a surfactant, suspendingagent, emulsifier and/or the like.

Examples of the excipient include lactose, glucose, starch, sucrose,microcrystalline cellulose, powdered glycyrrhiza, mannitol, sodiumhydrogen carbonate, calcium phosphate and calcium sulfate.

Examples of the binder include starch paste solutions, gum arabicsolutions, gelatin solutions, tragacanth solutions,carboxymethylcellulose solutions, sodium alginate solutions andglycerin.

Examples of the disintegrant include starch and calcium carbonate.

Examples of the lubricant include magnesium stearate, stearic acid,calcium stearate and purified talc.

Examples of the sweetener include glucose, fructose, invert sugar,sorbitol, xylitol, glycerin and simple syrup.

Examples of the surfactant include sodium lauryl sulfate, polysorbate80, sorbitan monofatty acid ester and polyoxyl 40 stearate.

Examples of the suspending agent include gum arabic, sodium alginate,sodium carboxymethylcellulose, methyl cellulose and bentonite.

Examples of the emulsifier include gum arabic, tragacanth, gelatin andpolysorbate 80.

Further, in cases where the drug containing Compound (I) is formulatedinto the above-described dosage form, a coloring agent, preservative,aromatic, corrigent, stabilizer, thickener and/or the like, which arecommonly used in the field of drug formulation, may be added.

The daily dose of the formulation varies depending on the conditions andthe body weight of the patient, type of the compound, administrationroute and the like, and is preferably 1 mg to 1000 mg in the case oforal administration to an adult (about 60 kg body weight), which isadministered in one time or dividedly in several times. In cases wherethe formulation is parenterally administered, the daily dose ispreferably 0.01 mg to 100 mg per 1 kg body weight, which isintravenously administered.

Compound (I) may also be used after blending with, or in combinationwith, another drug in an appropriate amount to complement or enhance thetherapeutic or prophylactic effect, or to reduce the dose. Compound (I)may be used in combination with, for example, the following drugs.

Examples of antitussive agents, expectorants and antitussive expectorantagents include dextromethorphan, benproperine, dimemorfan, clofedanol,ephedrine, huscode, fominoben, methylephedrine, acetylcysteine,ambroxol, carbocisteine, bromhexine, eprazinone, cherry bark extract,codeine, dihydrocodeine and tipepidine.

Examples of bronchodilators include clenbuterol, cromoglycate,salbutamol, salmeterol, tulobuterol, theophylline and procaterol.

Examples of antipeptic ulcer drugs include azulene, aldioxa,irsogladine, ecabet, omeprazole, ornoprostil, cimetidine, sucralfate,sulpiride, cetraxate and famotidine.

Examples of antibiotics include amoxicillin, azithromycin, erythromycin,clarithromycin, tetracycline and doxycycline.

Examples of narcotic analgesics include opium alkaloid, ethylmorphine,oxycodone, morphine, cocaine, fentanyl and pethidine.

EXAMPLES

Our compounds and methods will now be described in more detail withreference to Reference Examples and Examples. However, the disclosure isnot limited thereto.

The names of solvents in the parentheses set forth in NMR data indicatethe solvents used for the measurements.

JNM-AL400 type nuclear magnetic resonance apparatus manufactured by JEOLLTD, was used for measuring 400 MHz NMR spectrum. Chemical shifts werereferenced to tetramethylsilane and expressed in 8 (unit: ppm). Eachsignal was expressed in s (singlet), d (doublet), t (triplet), q(quartet), quint (quintet), sept (septet), m (multiplet), br (broad), dd(doublet of doublets), dt (doublet of triplets), ddd (doublet of doubletof doublets), dq (doublet of quartets), td (triplet of doublets) or tt(triplet of triplets). IR spectrum was measured using FT/IR-410manufactured by JASCO Corporation, and ESI-MS spectrum was measuredusing Micromass ZQ2K manufactured by Waters or 1200LC/MSD manufacturedby Agilent Technology. All the solvents used were commerciallyavailable. YFLC W-prep2XY manufactured by Yamazen Corporation was usedfor flash chromatography.

The raw materials of the compounds and synthesis of the intermediatesare described as Reference Examples in the following. Among thecompounds used in the synthesis of the compounds of Reference Examples,for the compounds whose synthesis method is not described, commerciallyavailable compounds were used.

Reference Example 1 8-Ethynyl-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of trimethylsilylacetylene (27.1 mL, 0.192 mol) intetrahydrofuran (300 mL), 2.77 M n-butyllithium (solution in n-hexane,69.3 mL, 0.192 mol) was added dropwise at −76° C. for 30 minutes, andthe obtained solution was stirred at the same temperature for 30minutes. A solution of 1,4-dioxaspiro[4.5]decan-8-one (25.0 g, 0.160mol) in tetrahydrofuran (100 mL) was added dropwise at −74° C. for 30minutes, and the obtained solution was stirred at the same temperaturefor 1 hour and 30 minutes. The reaction solution was poured intosaturated aqueous ammonium chloride solution and the resulting solutionwas extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure.

Methanol (320 mL) was added to the residue to dissolve it, and potassiumcarbonate (55.3 g, 0.400 mol) was added thereto. The resulting solutionwas stirred at room temperature for 2 hours and the obtained reactionsolution was concentrated under reduced pressure. Distilled water wasadded to the residue and the resultant was extracted with ethyl acetate.The organic layer was washed with distilled water and brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the captioned compound (29.1 g, 0.160 mol, 100%) aswhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.75-2.03 (9H, m), 2.49 (1H, m), 3.95 (4H,s).

ESI-MS: m/z=165 (M−OH)⁺

Reference Example 2 1-(3-Hydroxy-3-(p-tolyl)propyn-1-yl)cyclohexanol

To a solution of 1-ethynylcyclohexanol (500 mg, 4.02 mmol) intetrahydrofuran (20 mL), 2.77 M n-butyllithium (solution in n-hexane,3.6 mL, 9.90 mmol) was added dropwise at −78° C., and the obtainedsolution was stirred at the same temperature for 1 hour. To the reactionsolution, p-tolualdehyde (0.52 mL, 4.40 mmol) was added at −78° C., andthe obtained solution was allowed to warm gradually to room temperaturewith stirring. To the reaction solution, distilled water and 1 Mhydrochloric acid were added to make the mixture acidic, and theresultant was extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography (silica gel,n-hexane/ethyl acetate) to obtain the captioned compound (598 mg, 2.44mmol, 61%) as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.18-1.30 (1H, m), 1.47-1.74 (7H, m),1.89-1.98 (2H, m), 2.08 (1H, brs), 2.22 (1H, brs), 2.36 (3H, s), 5.47(1H, s), 7.19 (2H, d, J=8.0 Hz), 7.43 (2H, d, J=8.0 Hz).

ESI-MS: m/z=227 (M−OH)⁺

Reference Example 38-(3-Hydroxy-3-(p-tolyl)propyn-1-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (ReferenceExample 1) (15.0 g, 82.3 mmol) in tetrahydrofuran (165 mL), 2.77 Mn-butyllithium (solution in n-hexane, 62.4 mL, 172.9 mmol) was addeddropwise at −72° C. for 25 minutes, and the obtained solution wasstirred at the same temperature for 30 minutes. Thereafter,p-tolualdehyde (10.2 mL, 86.4 mmol) was added dropwise at −72° C. for 5minutes, and the obtained solution was stirred at the same temperaturefor 30 minutes. The reaction solution was allowed to warm to roomtemperature and poured into saturated aqueous ammonium chloridesolution. The reaction solution was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified byflash chromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (17.7 g, 58.5 mmol, 71%) as an amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.72-1.85 (4H, m), 1.90-2.04 (4H, m), 2.35(3H, s), 2.55 (1H, s), 2.78 (1H, d, J=6.0 Hz), 3.93 (4H, s), 5.44 (1H,d, J=6.0 Hz), 7.17 (2H, d, J=8.0 Hz), 7.40 (2H, d, J=8.0 Hz).

ESI-MS: m/z=285 (M−OH)⁺

Reference Example 48-(3-Hydroxy-3-(4-methoxyphenyl)propyn-1-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (ReferenceExample 1) (5.02 g, 27.6 mmol) in tetrahydrofuran (100 mL), 2.63 Mn-butyllithium (solution in n-hexane, 22.0 mL, 57.9 mmol) was addeddropwise at −72° C. for 15 minutes, and the obtained solution wasstirred at the same temperature for 60 minutes. Thereafter,4-methoxyaldehyde (3.52 mL, 28.9 mmol) was added dropwise at −72° C. for10 minutes, and the obtained solution was stirred at the sametemperature for 60 minutes. The reaction solution was allowed to warm toroom temperature and poured into saturated aqueous ammonium chloridesolution. The reaction solution was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified byflash chromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (7.46 g, 23.4 mmol, 85%) as an amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.73-1.85 (4H, m), 1.91-2.04 (4H, m), 2.32(1H, s), 2.52 (1H, d, J=6.1 Hz), 3.81 (3H, s), 3.94 (4H, s), 5.44 (1H,d, J=6.1 Hz), 6.89 (2H, d, J=8.5 Hz), 7.44 (2H, d, J=8.5 Hz).

Reference Example 58-(3-(4-Chlorophenyl)-3-hydroxypropyn-1-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (ReferenceExample 1) (5.03 g, 27.6 mmol) in tetrahydrofuran (100 mL), 2.63 Mn-butyllithium (solution in n-hexane, 22.1 mL, 57.9 mmol) was addeddropwise at −72° C. for 15 minutes, and the obtained solution wasstirred at the same temperature for 60 minutes. Thereafter,4-chlorobenzaldehyde (4.06 g, 28.9 mmol) was added dropwise at −72° C.for 10 minutes, and the obtained solution was stirred at the sametemperature for 60 minutes. The reaction solution was allowed to warm toroom temperature and poured into saturated aqueous ammonium chloridesolution. The reaction solution was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified byflash chromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (8.13 g, 25.2 mmol, 91%) as an amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.68-1.81 (4H, m), 1.86-1.90 (4H, m), 3.55(1H, s), 3.90 (4H, s), 4.03 (1H, d, J=4.2 Hz), 5.41 (1H, d, J=4.2 Hz),7.28 (2H, d, J=8.3 Hz), 7.41 (2H, d, J=8.3 Hz).

The following compounds were prepared in the same manner as describedabove.

TABLE 3 Reference Example Structural Formula Compound Data 6

¹H-NMR (400 MHz, CDCl₃) δ: 1.71-1.84 (4H, m), 1.88- 2.03 (4H, m),2.65-3.31 (2H, m), 3.91 (4H, s), 5.47 (1H, d, J = 5.2 Hz), 7.29-7.38(3H, m), 7.51 (2H, d, J = 8.4 Hz). ESI-MS: m/z = 271 (M − OH)⁺ 7

¹H-NMR (400 MHz, CDCl₃) δ: 1.69-1.85 (4H, m), 1.86- 2.02 (4H, m),2.40-3.12 (2H, m), 3.91 (4H, d, J = 1.2 Hz), 5.46 (1H, m), 7.04 (2H, dt,J = 7.6, 8.4 Hz), 7.49 (2H, dd, J = 5.2, 7.6 Hz). ESI-MS: m/z = 289 (M −OH)⁺ 8

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.85 (4H, m), 1.90- 2.02 (4H, m), 2.36(3H, s), 2.36-2.72 (2H, m), 3.93 (4H, s), 5.44 (1H, d, J = 4.8 Hz), 7.13(1H, d, J = 7.6 Hz), 7.26 (1H, t, J = 7.6 Hz), 7.30 (1H, d, J = 7.6 Hz),7.33 (1H, s). ESI-MS: m/z = 285 (M − OH)⁺ 9

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.85 (4H, m), 1.86- 2.02 (4H, m), 2.41(1H, s), 2.49 (3H, s), 2.71 (1H, s), 3.97 (4H, s), 5.44 (1H, m), 7.25(2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.4 Hz). ESI-MS: m/z = 317 (M −OH)⁺ 10

¹H-NMR (400 MHz, CDCl₃) δ: 1.69-1.84 (6H, m), 1.90- 2.01 (4H, m), 3.06(3H, s), 3.94 (4H, s), 5.57 (1H, d, J = 5.4 Hz), 7.72 (2H, d, J = 8.3Hz), 7.93 (2H, d, J = 8.3 Hz). ESI-MS: m/z = 349 (M − OH)⁺ 11

¹H-NMR (400 MHz, CD₃OD) δ: 1.73-1.76 (4H, m), 1.82- 1.94 (4H, m), 2.43(3H, s), 3.91-3.95 (5H, m), 5.61 (1H, d, J = 1.6 Hz), 7.15-7.20 (3H, m),7.59-7.61 (1H, m). ESI-MS: m/z = 285 (M − OH)⁺ 12

¹H-NMR (400 MHz, CDCl₃) δ: 1.72-1.85 (4H, m), 1.90- 2.04 (4H, m), 2.42(1H, s), 3.25 (1H, d, J = 2.4 Hz), 3.94 (4H, s), 4.02 (3H, s), 5.65 (1H,d, J = 2.4 Hz), 6.92 (1H, dd, J = 5.2, 7.2 Hz), 7.80 (1H, dd, J = 2.4,7.2 Hz), 8.13 (1H, dd, J = 2.4, 5.2 Hz). ESI-MS: m/z = 302 (M − OH)⁺ 13

¹H-NMR (400 MHz, CDCl₃) δ: 1.63 (1H, s), 1.75-1.83 (4H, m), 1.95-2.05(4H, m), 2.62 (1H, s), 3.94 (4H, s), 5.56 (1H, s), 7.64 (4H, s). ESI-MS:m/z = 339 (M − OH)⁺

Reference Example 14 3-(1-Hydroxycyclohexyl)-1-(p-tolyl)-2-propyn-1-one

To a solution of 1-(3-hydroxy-3-(p-tolyl)propyn-1-yl)cyclohexanol(Reference Example 2) (593 mg, 2.42 mmol) in dichloromethane (20 mL),manganese dioxide (1.15 g, 13.2 mmol) was added, and the obtainedsolution was stirred at room temperature for 5 hours. The reactionsolution was filtered through Celite and the filtrate was concentratedunder reduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(534 mg, 2.20 mmol, 91%) as a light yellow oily product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.28-1.39 (1H, m), 1.55-1.84 (7H, m),2.02-2.11 (2H, m), 2.23 (1H, brs), 2.43 (3H, s), 7.28 (2H, d, J=8.0 Hz),8.02 (2H, d, J=8.0 Hz).

Reference Example 153-(8-Hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)-2-propyn-1-one

To a solution of8-(3-hydroxy-3-(p-tolyl)propyn-1-yl)-1,4-dioxaspiro[4.5]decan-8-ol(Reference Example 3) (17.5 g, 57.9 mmol) in dichloromethane (289 mL),manganese dioxide (29.6 g, 289 mmol) was added, and the obtainedsolution was stirred at room temperature for 15 hours. The reactionsolution was filtered through Celite and the filtrate was concentratedunder reduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(14.3 g, 47.6 mmol, 82%) as an oily product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.79-1.85 (2H, m), 1.87-1.93 (2H, m),2.04-2.15 (4H, m), 2.20 (1H, s), 2.43 (3H, s), 3.97 (4H, s), 7.28 (2H,d, J=8.0 Hz), 8.00 (2H, d, J=8.0 Hz).

ESI-MS: m/z=284 (M−OH)⁺

Reference Example 163-(8-Hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(6-methylpyridin-3-yl)-2-propyn-1-one

To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (ReferenceExample 1) (592 mg, 3.25 mmol) in tetrahydrofuran (6 mL), 2.63 Mn-butyllithium (solution in n-hexane, 2.6 mL, 6.82 mmol) was addeddropwise at −78° C. for 5 minutes, and the obtained solution was stirredat the same temperature for 30 minutes. Thereafter, a solution ofN-methoxy-N-methyl-6-methylnicotinamide (614.5 mg, 3.41 mmol) intetrahydrofuran (5 ml) was added dropwise at −78° C. for 20 minutes, andthe obtained solution was stirred at the same temperature for 30minutes. The reaction solution was allowed to warm to room temperatureand poured into saturated aqueous ammonium chloride solution. Thereaction solution was extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (626.3 mg, 2.08 mmol, 65%) as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.76-1.83 (2H, m), 1.87-1.94 (2H, m),2.04-2.10 (2H, m), 2.12-2.19 (2H, m), 2.30 (1H, s), 2.66 (3H, s), 3.97(4H, s), 7.29 (1H, d, J=8.0 Hz), 8.22 (1H, dd, 2.4, 8.0 Hz), 9.21 (1H,d, J=2.4 Hz).

ESI-MS: m/z=284 (M−OH)⁺

Reference Example 173-(8-Hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-methoxyphenyl)-2-propyn-1-one

To a solution of8-(3-hydroxy-3-(4-methoxyphenyl)propyn-1-yl)-1,4-dioxaspiro[4.5]decan-8-ol(Reference Example 4) (7.10 g, 22.3 mmol) in dichloromethane (100 mL),manganese dioxide (9.69 g, 112 mmol) was added, and the obtainedsolution was stirred at room temperature for 18 hours. The reactionsolution was filtered through Celite and the filtrate was concentratedunder reduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(5.45 g, 17.2 mmol, 77%) as an oily product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.78-1.93 (4H, m), 2.03-2.17 (4H, m), 2.27(1H, s), 3.89 (3H, s), 3.97 (4H, s), 6.95 (2H, d, J=9.0 Hz), 8.08 (2H,d, J=9.0 Hz).

ESI-MS: m/z=299 (M−OH)⁺

Reference Example 181-(4-Chlorophenyl)-3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-2-propyn-1-one

To a solution of8-(3-(4-chlorophenyl)-3-hydroxypropyn-1-yl)-1,4-dioxaspiro[4.5]decan-8-ol(Reference Example 5) (7.70 g, 23.9 mmol) in dichloromethane (120 mL),manganese dioxide (10.4 g, 119 mmol) was added, and the obtainedsolution was stirred at room temperature for 18 hours. The reactionsolution was filtered through Celite and the filtrate was concentratedunder reduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(5.45 g, 17.0 mmol, 71%) as an oily product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.77-1.94 (4H, m), 2.04-2.19 (4H, m), 2.15(1H, s), 3.98 (4H, s), 7.47 (2H, d, J=8.5 Hz), 8.04 (2H, d, J=8.5 Hz).

ESI-MS: m/z=303 (M−OH)⁺

The following compounds were prepared in the same manner as describedabove.

TABLE 4 Reference Example Structural Formula Compound Data 19

¹H-NMR (400 MHz, CDCl₃) δ: 1.78-1.94 (4H, m), 2.04- 2.20 (4H, m), 2.33(1H, s), 3.97 (4H, s), 7.49 (2H, t, J = 7.2 Hz), 7.62 (1H, t, J = 7.2Hz), 7.69 (2H, d, J = 7.2 Hz). ESI-MS: m/z = 269 (M − OH)⁺ 20

¹H-NMR (400 MHz, CDCl₃) δ: 1.74-1.94 (4H, m), 2.05- 2.19 (4H, m),2.60-2.82 (1H, m), 3.97 (4H, s), 7.14 (2H, dd, J = 7.6, 8.4 Hz), 7.49(2H, dd, J = 5.2, 7.6 Hz). ESI-MS: m/z = 287 (M − OH)⁺ 21

¹H-NMR (400 MHz, CDCl₃) δ: 1.77-1.94 (4H, m), 2.04- 2.18 (4H, m), 2.20(1H, s), 2.43 (3H, s), 3.97 (4H, s), 7.37 (1H, t, J = 7.6 Hz), 7.44 (1H,d, J = 7.6 Hz), 7.91 (1H, s), 7.92 (1H, d, J = 7.6 Hz). ESI-MS: m/z =283 (M − OH)⁺ 22

¹H-NMR (400 MHz, CDCl₃) δ: 1.77-1.94 (4H, m), 2.02- 2.18 (4H, m), 2.05(1H, s), 2.54 (3H, s), 3.97 (4H, s), 7.27 (2H, d, J = 8.8 Hz), 8.00 (2H,d, J = 8.8 Hz). ESI-MS: m/z = 315 (M − OH)⁺ 23

¹H-NMR (400 MHz, CDCl₃) δ: 1.77-1.83 (2H, m), 1.89- 1.95 (2H, m),2.05-2.20 (4H, m), 2.37 (1H, s), 3.10 (3H, s), 3.98 (4H, s), 8.08 (2H,d, J = 8.1 Hz), 8.29 (2H, d, J = 8.1 Hz). ESI-MS: m/z = 347 (M − OH)⁺ 24

¹H-NMR (400 MHz, CDCl3) δ: 1.77-1.83 (2H, m), 1.86- 1.92 (2H, m),2.02-2.08 (2H, m), 2.01-2.14 (2H, m), 2.62 (3H, s), 3.97 (4H, s),7.24-7.26 (1H, m), 7.33 (1H, dd, J = 7.2, 7.6 Hz), 7.45 (1H, dd, J =7.2, 8.0 Hz), 8.16 (1H, d, J = 8.0 Hz). ESI-MS: m/z = 283 (M − OH)⁺ 25

¹H-NMR (400 MHz, CDCl3) δ: 1.79-1.91 (4H, m), 2.01- 2.15 (4H, m), 2.38(1H, s), 3.97 (4H, s), 4.08 (3H, s), 6.99- 7.02 (1H, m), 8.25-8.28 (1H,m), 8.36-8.37 (1H, m). 26

¹H-NMR (400 MHz, CDCl3) δ: 1.81-1.84 (2H, m), 1.89- 1.94 (2H, m),2.09-2.17 (4H, m), 2.38 (1H, s), 3.98 (4H, s), 7.76 (2H, d, J = 8.0 Hz),8.21 (2H, d, J = 8.0 Hz). 27

¹H-NMR (400 MHz, CDCl3) δ: 1.76-1.95 (4H, m), 2.04- 2.20 (5H, m), 2.36(3H, d, J = 2.0 Hz), 3.97 (4H, s), 7.31 (1H, t, J = 8.0 Hz), 7.71 (1H,d, J = 10.0 Hz), 7.81 (1H, d, J = 8.0 Hz). ESI-MS: m/z = 319 (M + H)⁺ 28

¹H-NMR (400 MHz, CDCl3) δ: 1.75-1.96 (4H, m), 2.03- 2.25 (4H, m),2.47-2.60 (1H, m), 3.98 (4H, s), 7.77-7.82 (2H, m), 8.16-8.23 (2H, m).ESI-MS: m/z = 312 (M + H)⁺ 29

¹H-NMR (400 MHz, CDCl3) δ: 1.26 (3H, t, J = 7.6 Hz), 1.78-1.94 (4H, m),2.03-2.19 (4H, m), 2.27 (1H, br), 2.72 (2H, q, J = 7.6 Hz), 3.98 (4H,s), 7.30 (2H, d, J = 8.4 Hz), 8.03 (2H, d, J = 8.4 Hz). ESI-MS: m/z =315 (M + H)⁺

Reference Example 308-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 4-methoxyphenylhydrazine hydrochloride (7.35 g, 42.1mmol) in ethanol (76.6 mL), triethylamine (5.87 mL, 42.1 mmol) was addeddropwise, and the obtained solution was stirred at room temperature for30 minutes. To the reaction solution, a solution of3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)-2-propyn-1-one(Reference Example 15) (11.5 g, 38.3 mmol) in ethanol (76.6 mL) wasadded dropwise, and the obtained solution was stirred at roomtemperature for 15 hours. Thereafter, the reaction solution wasconcentrated under reduced pressure. Water was added to the residue andthe resultant was extracted with ethyl acetate. The organic layer waswashed with 1 M hydrochloric acid, distilled water and brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the captioned compound (14.7 g, 35.0 mmol, 91%) as anamorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.71-1.74 (2H, m), 1.99-2.25 (6H, m), 2.33(3H, s), 2.71 (1H, s), 3.81 (3H, s), 3.96-4.01 (4H, m), 6.39 (1H, s),6.84 (2H, d, J=8.0 Hz), 7.09 (4H, s), 7.21 (2H, d, J=8.0 Hz).

ESI-MS: m/z=421 (M+H)⁺

Reference Example 318-(1-(4-Methoxyphenyl)-5-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8

To a solution of 4-methoxyphenylhydrazine hydrochloride (359 mg, 2.06mmol) in ethanol (4 mL), triethylamine (286 μL, 2.06 mmol) was addeddropwise, and the obtained solution was stirred at room temperature for30 minutes. To the reaction solution, a solution of3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(6-methylpyridin-3-yl)-2-propyn-1-one(Reference Example 16) (563.7 mg, 1.87 mmol) in ethanol (5.4 mL) wasadded dropwise, and the obtained solution was stirred at roomtemperature for 22 hours. Thereafter, the reaction solution wasconcentrated under reduced pressure. Water was added to the residue andthe resultant was extracted with ethyl acetate. The organic layer waswashed with distilled water and brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the captioned compound (177 mg, 0.42 mmol, 22%) as an amorphousproduct.

¹H-NMR (400 MHz, CDCl₃) δ: 1.72-1.75 (2H, m), 2.00-2.03 (2H, m),2.07-2.14 (2H, m), 2.19-2.26 (2H, m), 2.55 (3H, s), 2.65 (1H, s), 3.81(3H, s), 3.96-4.03 (4H, m), 6.47 (1H, s), 6.86 (2H, d, J=8.8 Hz), 7.06(1H, d, J=8.0 Hz), 7.20 (2H, d, J=8.8 Hz), 7.33 (1H, dd, J=2.2, 8.0 Hz),8.40 (1H, d, J=2.2 Hz).

ESI-MS: m/z=422 (M+H)⁺

Reference Example 328-(1,5-Bis(4-methoxyphenyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-methoxyphenyl)-2-propyn-1-one(Reference Example 17) (700 mg, 2.24 mmol) in ethanol (4.5 mL), asolution of 4-methoxyphenylhydrazine hydrochloride (470 mg, 2.69 mmol)and triethylamine (0.74 mL, 5.41 mmol) in ethanol (4.5 mL) was added,and the obtained solution was stirred at room temperature for 20 hours.The reaction solution was concentrated under reduced pressure. Distilledwater was added to the residue and the resultant was extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the captioned compound (864 mg, 1.98 mmol, 88%) as a whiteamorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.68-1.77 (2H, m), 1.96-2.26 (6H, m), 2.70(1H, brs), 3.80 (3H, s), 3.81 (3H, s), 3.94-4.04 (4H, m), 6.37 (1H, s),6.81 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 7.13 (2H, d, J=8.8 Hz),7.21 (2H, d, J=8.8 Hz).

ESI-MS: m/z=437 (M+H)⁺

Reference Example 338-(5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 4-methoxyphenylhydrazine hydrochloride (457 mg, 2.62mmol) in ethanol (4.4 mL), triethylamine (0.730 mL, 5.24 mmol) was addeddropwise, and the obtained solution was stirred at room temperature for30 minutes. To the reaction solution, a solution of1-(4-chlorophenyl)-3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-2-propyn-1-one(Reference Example 18) (700 mg, 2.18 mmol) in ethanol (4.4 mL) was addeddropwise, and the obtained solution was stirred at room temperature for14 hours. Thereafter, the reaction solution was concentrated underreduced pressure. Water was added to the residue and the resultant wasextracted with ethyl acetate. The organic layer was washed with 1 Mhydrochloric acid, distilled water and brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the captioned compound (756 mg, 1.71 mmol, 79%) as anamorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.69-1.76 (2H, m), 1.97-2.25 (6H, m), 2.66(1H, brs), 3.82 (3H, s), 3.94-4.03 (4H, m), 6.43 (1H, s), 6.85-6.87 (2H,m), 7.13 (2H, d, J=8.4 Hz), 7.19 (2H, d, J=8.4 Hz), 7.25-7.27 (2H, m).

ESI-MS: m/z=441 (M+H)⁺

Reference Example 348-(1-(4-Chlorophenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 4-chlorophenylhydrazine hydrochloride (418 mg, 2.33mmol) in ethanol (4.8 mL), triethylamine (5.87 mL, 42.1 mmol) was addeddropwise, and the obtained solution was stirred at room temperature for30 minutes. To the reaction solution, a solution of3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)-2-propyn-1-one(Reference Example 15) (698 mg, 2.32 mmol) in ethanol (4.7 mL) was addeddropwise, and the obtained solution was stirred at room temperature for14 hours. Thereafter, the reaction solution was concentrated underreduced pressure. Water was added to the residue and the resultant wasextracted with ethyl acetate. The organic layer was washed withdistilled water and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (948 mg, 2.23 mmol, yield: 96%) as an amorphousproduct.

¹H-NMR (400 MHz, CDCl₃) δ: 1.71-1.75 (2H, m), 1.98-2.14 (4H, m),2.17-125 (2H, m), 2.36 (3H, s), 2.62 (1H, s), 3.96-4.03 (4H, m), 6.41(1H, s), 7.09 (2H, d, J=8.0 Hz), 7.13 (2H, d, J=8.0 Hz), 7.22-7.30 (4H,m).

ESI-MS: m/z=407 (M−OH)⁺

The following compounds were prepared in the same manner as describedabove.

TABLE 5 Reference Example Structural Formula Compound Data 35

¹H-NMR (400 MHz, CDCl₃) δ: 1.72-1.75 (2H, m), 1.99 (3H, s), 2.02-108(2H, m), 2.11-2.15 (2H, m), 2.18-2.26 (2H, m), 2.70 (1H, s), 3.75 (3H,s), 3.95-4.03 (4H, m), 6.31 (1H, s), 6.75 (2H, d, J = 8.8 Hz), 7.10-7.12(2H, m), 7.15- 7.19 (4H, m). ESI-MS: m/z = 421 (M + H)⁺ 36

¹H-NMR (400 MHz, CDCl₃) δ: 1.72-1.75 (2H, m), 2.00- 2.13 (4H, m),239-226 (2H, m), 2.69 (1H, s), 3.07 (3H, s), 3.83 (3H, s), 3.96-4.02(4H, m), 6.55 (1H, s), 6.88 (2H, d, J = 8.8 Hz), 7.18 (2H, d, J = 8.8Hz), 7.40 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz). ESI-MS: m/z =467 (M − OH)⁺ 37

¹H-NMR (400 MHz, CDCl₃) δ: 1.68-1.76 (2H, m), 1.96- 2.26 (6H, m), 2.67(1H, s), 3.94-4.03 (4H, m), 6.45 (1H, s), 7.00-7.17 (2H, m), 7.10-7.15(2H, m), 7.21-7.31 (4H, m). ESI-MS: m/z = 429 (M + H)⁺ 38

¹H-NMR (400 MHz, CDCl₃) δ: 1.69-1.76 (2H, m), 2.16- 2.25 (2H, m),1.96-2.23 (4H, m), 2.63 (1H, s), 3.94-4.03 (4H, m), 6.45 (1H, s), 7.14(2H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.29-7.32 (4H, m).ESI-MS: m/z = 445 (M + H)⁺ 39

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.76 (2H, m), 1.98- 2.14 (4H, m),2.18-2.25 (2H, m), 2.68 (1H, s), 3.95-4.02 (4H, m), 6.45 (1H, s),7.13-7.15 (2H, m), 7.25-7.37 (7H, m). ESI-MS: m/z = 411 (M + H)⁺ 40

¹H-NMR (400 MHz, CDCl₃) δ: 1.69-1.77 (2H, m), 1.99- 2.12 (4H, m),2.18-2.26 (2H, m), 2.57 (1H, brs), 3.96-4.02 (4H, m), 6.49-6.51 (1H, m),7.07-7.10 (2H, m), 7.23-7.37 (4H, m), 7.43-7.45 (1H, m). ESI-MS: m/z =479 (M + H)⁺ 41

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.76 (2H, m), 1.98- 2.14 (4H, m),2.17-2.26 (2H, m), 2.29 (3H, s), 2.74 (1H, brs), 3.80 (3H, s), 3.95-4.02(4H, m), 6.41 (1H, s), 6.84 (2H, d, J = 8.8 Hz), 6.92-6.96 (1H, m),7.08-7.17 (3H, m), 7.21 (2H, d, J = 8.8 Hz). ESI-MS: m/z = 421 (M + H)⁺42

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.76 (2H, m), 1.98- 2.04 (2H, m),2.06-2.14 (2H, m), 2.18-2.25 (2H, m), 2.35 (3H, s), 2.62 (1H, s),3.96-4.03 (4H, m), 6.41 (1H, s), 6.99- 7.04 (2H, m), 7.08 (2H, d, J =8.0 Hz), 7.11 (2H, d, J = 8.0 Hz), 7.25-7.28 (2H, m). ESI-MS: m/z = 391(M − OH)⁺ 43

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.76 (2H, m), 1.98- 2.04 (2H, m),2.07-2.14 (2H, m), 2.18-2.25 (2H, m), 2.34 (3H, s), 2.35 (3H, s), 2.70(1H, s), 3.95-4.02 (4H, m), 6.40 (1H, s), 7.08-7.11 (4H, m), 7.12 (2H,d, J = 8.4 Hz), 7.17 (2H, d, J = 8.4 Hz). ESI-MS: m/z = 387 (M − OH)⁺ 44

¹H-NMR (400 MHz, CDCl₃) δ: 1.71-1.77 (2H, m), 1.98- 2.05 (2H, m),2.07-2.14 (2H, m), 2.18-2.26 (2H, m), 2.34 (3H, s), 2.69 (1H, s),3.96-4.03 (4H, m), 6.42 (1H, s), 7.09- 7.11 (4H, m), 7.26-7.35 (5H, m).ESI-MS: m/z = 373 (M − OH)⁺ 45

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.76 (2H, m), 1.98- 2.08 (2H, m),2.09-2.14 (2H, m), 2.17-2.25 (2H, m), 2.66 (1H, s), 3.81 (3H, s),3.95-4.03 (4H, m), 6.41 (1H, s), 6.83- 6.87 (2H, m), 6.96-7.01 (2H, m),7.16-7.20 (4H, m). ESI-MS: m/z = 407 (M − OH)⁺ 46

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.76 (2H, m), 1.97- 2.08 (2H, m),2.09-2.14 (2H, m), 2.17-2.25 (2H, m), 2.59 (1H, s), 3.95-4.03 (4H, m),6.43 (1H, s), 6.99-7.05 (2H, m), 7.16-7.23 (4H, m), 7.28-7.32 (2H, m).ESI-MS: m/z = 411 (M − OH)⁺ 47

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.76 (2H, m), 1.98- 2.07 (2H, m),2.09-2.14 (2H, m), 2.17-2.25 (2H, m), 2.60 (1H, s), 3.95-4.03 (4H, m),6.43 (1H, s), 6.98-7.06 (4H, m), 7.15-7.19 (2H, m), 7.22-7.26 (2H, m).ESI-MS: m/z = 395 (M − OH)⁺ 48

¹H-NMR (400 MHz, CDCl₃) δ: 1.71-1.77 (2H, m), 1.99- 2.05 (2H, m),2.06-2.15 (2H, m), 2.18-2.26 (2H, m), 2.66 (1H, s), 3.95-4.03 (4H, m),6.43 (1H, s), 6.96-7.02 (2H, m), 7.16-7.21 (2H, m), 7.25-7.36 (5H, m).ESI-MS: m/z = 377 (M − OH)⁺ 49

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.76 (2H, m), 1.98- 2.05 (2H, m),2.06-2.14 (2H, m), 2.17-2.25 (2H, m), 2.35 (3H, s), 2.68 (1H, s),3.95-4.03 (4H, m), 6.41 (1H, s), 6.96- 7.02 (2H, m), 7.11-7.21 (6H, m).ESI-MS: m/z = 391 (M − OH)⁺ 50

¹H-NMR (400 MHz, CDCl₃) δ: 1.71-1.77 (2H, m), 1.98- 2.03 (2H, m),2.06-2.13 (2H, m), 2.18-2.26 (2H, m), 2.38 (3H, s), 2.60 (1H, s), 3.06(3H, s), 3.96-4.03 (4H, m), 6.47 (1H, s), 7.11 (2H, d, J = 8.0 Hz), 7.16(2H, d, J = 8.0 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.4 Hz).ESI-MS: m/z = 451 (M − OH)⁺ 51

¹H-NMR (400 MHz, CDCl₃) δ: 1.72-1.75 (2H, m), 2.02- 2.14 (4H, m),2.19-2.23 (2H, m), 2.66 (1H, s), 3.67 (3H, s), 3.79 (3H, s), 3.98-4.01(4H, m), 6.47 (1H, s), 6.80-6.88 (3H, m), 7.15-7.17 (2H, m), 7.44 (1H,dd, J = 2.0, 5.2 Hz), 8.15 (1H, dd, J = 2.0, 8.4 Hz). ESI-MS: m/z = 438(M + H)⁺ 52

¹H-NMR (400 MHz, CDCl3) δ: 1.60 (2H, m), 1.73 (2H, d, J = 12.4 Hz), 2.10(2H, td, J = 3.4, 12.8 Hz), 2.22 (2H, td, J = 3.9, 12.4 Hz), 3.80 (3H,s), 3.96-4.03 (4H, m), 6.44 (1H, s), 6.83-6.85 (2H, m), 7.18-7.22 (4H,m), 7.26-7.30 (3H, m). 53

¹H-NMR (400 MHz, CDCl3) δ: 1.73 (2H, d, J = 12.0 Hz), 2.01 (2H, d, J =12.4 Hz), 2.10 (2H, td, J = 3.2 Hz), 2.22 (2H, td, J = 3.2, J = 12.4Hz), 2.24 (3H, s), 3.96-4.03 (4H, m), 6.44 (1H, s), 7.12 (2H, d, J = 8.4Hz), 7.16 (2H, d, J = 8.8 Hz), 7.21-7.23 (2H, m), 7.27-7.30 (3H, m).ESI-MS: m/z = 391 (M + H)⁺ 54

¹H-NMR (400 MHz, CDCl3) δ: 1.73 (2H, d, J = 12.4 Hz), 1.99 (2H, d, J =12.4 Hz), 2.10 (2H, td, J = 3.2, 12.4 Hz), 2.21 (2H, td, J = 3.6, 12.4Hz), 2.25 (3H, s), 2.73 (1H, s), 3.80 (3H, s), 3.96-4.03 (4H, m), 6.37(1H, s), 6.82 (2H, m), 7.09-7.18 (6H, m). ESI-MS: m/z = 421 (M + H)⁺ 55

¹H-NMR (400 MHz, CDCl3) δ: 1.70 (2H, d, J = 13.6 Hz), 2.01 (2H, d, J =9.2 Hz), 2.10 (2H, td, J = 3.6, 12.8 Hz), 2.21 (2H, td, J = 3.6, 12.4Hz), 2.66 (1H, s), 3.80 (3H, s), 3.95- 4.03 (4H, m), 6.39 (1H, s), 6.83(2H, ddd, J = 9.2 Hz), 7.01 (2H, t, J = 8.8 Hz), 7.11 (2H, d, J = 8.8Hz), 7.26 (2H, t, J = 6.0 Hz). ESI-MS: m/z = 425 (M + H)⁺ 56

¹H-NMR (400 MHz, CDCl3) δ: 1.73 (2H, d, J = 12.4 Hz), 2.01 (2H, d, J =12.4 Hz), 2.10 (2H, td, J = 3.2, 12.8 Hz), 2.21 (2H, td, J = 3.2, 12.4Hz), 2.64 (1H, s), 3.82 (3H, s), 3.95-4.03 (4H, m), 6.40 (1H, s), 6.84(2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8 Hz),7.28 (2H, d, J = 8.8 Hz). ESI-MS: m/z = 441 (M + H)⁺ 57

¹H-NMR (400 MHz, CDCl3) δ: 1.70 (2H, d, J = 12.0 Hz), 2.01 (2H, d, J =8.8 Hz), 2.10 (2H, td, J = 4.0, 12.8 Hz), 2.21 (2H, td, J = 3.6, 12.4Hz), 2.71 (1H, s), 3.80 (3H, s), 3.92- 4.03 (4H, m), 6.39 (1H, s), 6.81(2H, d, J = 12.0 Hz), 7.13 (2H, d, J = 12.0 Hz), 7.22-7.35 (5H, m). 58

¹H-NMR (400 MHz, CDCl3) δ: 1.71-1.74 (4H, m), 1.96- 2.16 (4H, m), 2.87(1H, s), 3.81 (3H, s), 3.94-4.01 (4H, m), 6.52 (1H, s), 6.86 (2H, d, J =8.0 Hz), 7.19 (2H, d, J = 8.0 Hz), 7.32 (2H, d, J = 8.0 Hz), 7.54 (2H,d, J = 8.0 Hz). 59

¹H-NMR (400 MHz, CDCl3) δ: 1.23 (3H, t, J = 7.6 Hz), 1.69-1.76 (2H, m),1.98-2.26 (6H, m), 2.63 (2H, q, J = 7.6 Hz), 2.69 (1H, br), 3.81 (3H,s), 3.95-4.03 (4H, m), 6.40 (1H, s), 6.82-6.87 (2H, m), 7.12 (4H, s),7.19-7.24 (2H, m). ESI-MS: m/z = 425 (M + H)⁺ 60

¹H-NMR (400 MHz, CDCl₃) δ: 1.68-1.77 (2H, m), 1.97- 2.25 (6H, m), 2.35(3H, s), 2.64 (1H, s), 3.89 (3H, s), 3.94- 4.03 (4H, m), 6.40 (1H, s),6.87 (1H, t, J = 8.8 Hz), 6.94- 7.01 (1H, m), 7.07-7.13 (5H, m). ESI-MS:m/z = 425 (M + H)⁺ 61

¹H-NMR (400 MHz, CDCl₃) δ: 1.69-1.77 (2H, m), 1.97- 2.28 (9H, m), 2.64(1H, s), 3.82 (3H, s), 3.95-4.03 (4H, m), 6.41 (1H, s), 6.83-6.89 (4H,m), 7.08 (1H, t, J = 8.0 Hz), 7.18-7.27 (2H, m). ESI-MS: m/z = 439 (M +H)⁺ 62

¹H-NMR (400 MHz, CDCl₃) δ: 1.70-1.78 (2H, m), 1.97- 2.27 (6H, m), 2.38(3H, s), 2.54 (1H, s), 3.94-4.03 (4H, m), 6.45 (1H, s), 7.09-7.20 (4H,m), 7.40-7.44 (2H, m), 7.57- 7.62 (2H, m). ESI-MS: m/z = 416 (M + H)⁺ 63

¹H-NMR (400 MHz, CDCl₃) δ: 1.69-1.76 (2H, m), 1.97- 2.26 (6H, m), 2.56(1H, br), 3.83 (3H, s), 3.94-4.03 (4H, m), 6.52 (1H, s), 6.84-6.90 (2H,m), 7.14-7.20 (2H, m), 7.29- 7.33 (2H, m), 7.55-7.59 (2H, m). ESI-MS:m/z = 432 (M + H)⁺

The following compounds were prepared in the same manner as in Examples37-41 described below.

TABLE 6 Reference Example Structural Formula Compound Data 64

¹H-NMR (400 MHz, CDCl₃) δ: 1.99 (3H, s), 2.34-2.39 (5H, m), 2.42-2.43(1H, m), 2.87-2.96 (2H, m), 3.19 (1H, s), 3.76 (3H, s), 6.31 (1H, s),6.76 (2H, d, J = 8.8 Hz), 7.11-7.20 (5H, m), 7.25-7.28 (1H, m). ESI-MS:m/z = 377 (M + H)⁺ 65

¹H-NMR (400 MHz, CDCl₃) δ: 2.34-2.44 (6H, m), 2.86- 2.96 (3H, m), 3.07(3H, s), 3.83 (3H, s), 6.54 (1H, s), 6.90 (2H, d, J = 8.8 Hz), 7.19 (2H,d, J = 8.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.87 (2H, d, J = 8.8 Hz).ESI-MS: m/z = 441 (M + H)⁺ 66

¹H-NMR (400 MHz, CDCl₃) δ: 2.31-2.45 (6H, m), 2.82 (1H, s), 2.86-2.97(2H, m), 6.45 (1H, s), 7.03-7.10 (2H, m), 7.12-7.17 (2H, m), 7.22-7.33(4H, m). ESI-MS: m/z = 385 (M + H)⁺ 67

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.45 (6H, m), 2.75 (1H, s), 2.84-2.94(2H, m), 6.50 (1H, s), 7.09-7.12 (2H, m), 7.25-7.28 (2H, m), 7.34-7.36(2H, m), 7.46-7.48 (1H, m). ESI-MS: m/z = 435 (M + H)⁺ 68

¹H-NMR (400 MHz, CDCl₃) δ: 2.29-2.44 (9H, m), 2.86- 2.96 (2H, m), 3.00(1H, s), 3.81 (3H, s), 6.41 (1H, s), 6.86 (2H, d, J = 9.2 Hz), 6.93-6.97(1H, m), 7.09-7.19 (m, 3H), 7.21 (2H, d, J = 9.2 Hz). ESI-MS: m/z = 377(M + H)⁺ 69

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.36 (4H, m), 2.35 (3H, s), 2.38-2.44(2H, m), 2.87-2.96 (2H, m), 2.90 (1H, s), 6.41 (1H, s), 7.01 (2H, m),7.09 (2H, d, J = 8.4 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.23-7.30 (2H, m).ESI-MS: m/z = 365 (M + H)⁺ 70

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.37 (4H, m), 2.37- 2.45 (2H, m),2.87-2.96 (2H, m), 2.94 (1H, s), 3.82 (3H, s), 6.40 (1H, s), 6.85-6.89(2H, m), 6.97-7.03 (2H, m), 7.17- 7.21 (4H, m). ESI-MS: m/z = 381 (M +H)⁺ 71

¹H-NMR (400 MHz, CDCl₃) δ: 2.31-2.36 (4H, m), 2.38- 2.45 (2H, m), 2.85(1H, s), 2.87-2.96 (2H, m), 6.43 (1H, s), 7.01-7.07 (2H, m), 7.18-7.23(4H, m), 7.31-7.34 (2H, m). ESI-MS: m/z = 385 (M + H)⁺ 72

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.36 (4H, m), 2.39- 2.45(2H, m), 2.87(1H, s), 2.87-2.96 (2H, m), 6.42 (1H, s), 7.00-7.08 (4H, m), 7.16-7.21(2H, m), 7.23-7.28 (2H, m). ESI-MS: m/z = 369 (M + H)⁺ 73

¹H-NMR (400 MHz, CDCl₃) δ: 2.33-2.37 (4H, m), 2.38- 2.45 (2H, m),2.87-2.96 (2H, m), 2.94 (1H, s), 6.43 (1H, s), 6.98-7.03 (2H, m),7.17-7.22 (2H, m), 7.26-7.39 (5H, m). ESI-MS: m/z = 351 (M + H)⁺ 74

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.37 (4H, m), 2.37 (3H, s), 2.38-2.44(2H, m), 2.87-2.95 (2H, m), 2.94 (1H, s), 6.40 (1H, s), 6.97-7.03 (2H,m), 7.13-7.22 (6H, m). ESI-MS: m/z = 365 (M + H)⁺ 75

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.36 (4H, m), 2.39 (3H, s), 2.39-2.46(2H, m), 2.85 (1H, s), 2.88-2.96 (2H, m), 3.07 (3H, s), 6.46 (1H, s),7.12 (2H, d, J = 8.0 Hz), 7.18 (2H, d, J = 8.0 Hz), 7.51 (2H, d, J = 8.4Hz), 7.90 (2H, d, J = 8.4 Hz). ESI-MS: m/z = 425 (M + H)⁺ 76

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.43 (6H, m), 2.88- 2.95 (3H, m), 3.68(3H, s), 3.80 (3H, s), 6.47 (1H, s), 6.84 (2H, d, J = 8.8 Hz), 6.87-6.89(1H, m), 7.17 (2H, d, J = 8.8 Hz), 7.45-7.47 (1H, m), 8.15-8.17 (1H,m),. ESI-MS: m/z = 394 (M + H) 77

¹H-NMR (400 MHz, CDCl₃) δ: 2.31-2.43 (6H, m), 2.86- 2.93 (2H, m), 2.95(1H, s), 3.81 (3H, s), 6.38 (1H, s), 6.84 (2H, d, J = 8.8 Hz), 7.04 (2H,t, J = 8.8 Hz), 7.12 (2H, d, J = 8.80 Hz), 7.24-7.30 (2H, m). ESI-MS:m/z = 381 (M + H)⁺

Reference Example 781-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexane-cis-1,4-diyldiacetate

To a suspension of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexane-cis-1,4-diol(Example 2-B) (300 mg, 0.793 mmol) in dichloromethane (2.6 mL), aceticanhydride (0.187 mL, 1.98 mmol), pyridine (0.192 mL, 2.38 mmol) and4-dimethylaminopyridine (48.4 mg, 0.396 mmol) were added, and theobtained solution was stirred at room temperature for 60 hours. Again,4-dimethylaminopyridine (48.4 mg, 0.396 mmol) was added and theresulting solution was stirred at room temperature for an additional 6hours. The reaction was quenched by adding water to the reactionsolution, and the resulting solution was extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the captioned compound (297 mg, 0.642 mmol, 81%) as a whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.74-1.82 (2H, m), 1.92-1.98 (2H, m),2.01-2.08 (5H, m), 2.10 (3H, s), 2.32 (3H, s), 2.70-2.77 (2H, m), 3.80(3H, s), 4.80-4.89 (1H, m), 6.38 (1H, s), 6.83 (2H, d, J=8.8 Hz), 7.08(4H, s), 7.20 (2H, d, J=8.8 Hz).

ESI-MS: m/z=463 (M+H)⁺

Reference Example 79c-4-Methoxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-ylacetate

To a solution ofc-4-hydroxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-ylacetate (Comparative Example 26) (0.150 g, 0.357 mmol) inN,N-dimethylformamide (1.8 mL), 55% sodium hydride (23.4 mg, 0.535 mmol)and methyl iodide (29.0 μL, 0.464 mmol) were added with stirring underice-cooling, and the obtained solution was stirred at room temperaturefor 9 hours. The reaction was quenched by adding water to the reactionsolution with stirring under ice-cooling, and the resulting solution wasextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography (silica gel,n-hexane/ethyl acetate) to obtain the captioned compound (124 mg, 0.284mmol, 80%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.60-1.68 (2H, m), 1.94-2.03 (4H, m), 2.08(3H, s), 2.32 (3H, s), 2.69-2.76 (2H, m), 3.24-3.33 (1H, m), 3.39 (3H,s), 3.80 (3H, s), 6.37 (1H, s), 6.83 (2H, d, J=8.8 Hz), 7.08 (4H, s),7.20 (2H, d, J=8.8 Hz).

ESI-MS: m/z=435 (M+H)⁺

Reference Example 804-(4-Fluoro-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-c-4-hydroxy-cyclohexan-r-1-ylacetate

To a solution ofc-4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexane-r-1-ylacetate (Example 57) (130 mg, 0.309 mmol) in acetonitrile (3.09 mL),Selectfluor™ (120 mg, 0.340 mmol) was added, and the obtained solutionwas stirred at room temperature for 3 hours. Saturated aqueous sodiumthiosulfate solution was added to the reaction solution, and theresulting solution was extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (61 mg, 0.140 mmol, 45%) as a light yellow amorphousproduct.

¹H-NMR (400 MHz, CDCl₃) δ: 1.89-2.15 (11H, m), 2.35 (3H, m), 2.73 (1H,s), 3.81 (3H, s), 4.82-4.89 (1H, m), 6.84-6.86 (2H, m), 7.10-7.18 (6H,m).

ESI-MS: m/z=439 (M+H)⁺

Reference Example 811-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-4-oxo-cyclohexan-1-ylacetate

To a solution ofc-4-hydroxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-ylacetate (Comparative Example 26) (142 mg, 0.338 mmol) in dichloromethane(3.38 mL), Dess-Martin reagent (172 mg, 0.405 mmol) was added, and theobtained solution was stirred at 0° C. for 2 hours. The reactionsolution was filtered through Celite and the residue was purified byflash chromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (120 mg, 0.287 mmol, 85%) as a white amorphousproduct.

¹H-NMR (400 MHz, CDCl₃) δ: 2.13 (3H, s), 2.33 (3H, s), 2.44-2.52 (4H,m), 2.59-2.65 (2H, m), 2.93-2.96 (2H, m), 3.81 (3H, s), 6.45 (1H, s),6.84 (2H, d, J=8.8 Hz), 7.08 (4H, s), 7.20 (2H, d, J=8.8 Hz).

ESI-MS: m/z=419 (M+H)⁺

Reference Example 82c-4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexane-r-1-carbaldehyde

To a solution of (methoxymethyl)triphenylphosphonium chloride (546.3 mg,1.59 mmol) in tetrahydrofuran (1.3 mL), potassium tert-butoxide (178.7mg, 1.59 mmol) was added at −40° C., and the obtained solution wasstirred at the same temperature for 60 minutes. To the reactionsolution, a solution of4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-1-one(Example 37) (200 mg, 0.53 mmol) in tetrahydrofuran (1.35 mL) was addeddropwise at −40° C., and the obtained solution was stirred at roomtemperature for 1.5 hours. To the reaction solution, 6 M aqueoushydrochloric acid solution was added at 0° C., and the obtained solutionwas stirred for 12 hours. Distilled water was added to the reactionsolution and the resulting solution was extracted with ethyl acetate.The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (87.5 mg, 0.23 mmol, 42%) as a colorless oilyproduct.

¹H-NMR (400 MHz, CDCl₃) δ: 1.88-1.96 (6H, m), 2.09-2.11 (2H, m),2.25-2.36 (5H, m), 3.80 (3H, s), 6.39 (1H, s), 6.84 (2H, d, J=8.8 Hz),7.09-7.14 (4H, m), 7.20 (2H, d, J=8.8 Hz), 9.66 (1H, d, J=2.0 Hz).

ESI-MS: m/z=391 (M+H)⁺

Reference Example 83 Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate

To a solution of ethyl 4-oxocyclohexanecarboxylate (10.0 g, 58.8 mmol)in toluene (196 mL), ethylene glycol (3.6 mL, 64.6 mmol) andp-toluenesulfonic acid monohydrate (1.12 g, 5.88 mmol) were added, andthe obtained solution was heated to reflux at 150° C. The resultingsolution was stirred for 18 hours. The reaction was quenched by adding asaturated sodium bicarbonate solution to the reaction solution, and theresulting solution was extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (12.3 g, 57.4 mmol, 98%) as a colorless oilycompound.

¹H-NMR (400 MHz, CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 1.51-1.61 (2H, m),1.75-1.86 (4H, m), 1.90-1.98 (2H, m), 2.29-2.38 (1H, s), 3.95 (4H, s),4.13 (2H, q, J=7.2 Hz).

ESI-MS: m/z=215 (M+H)⁺

Reference Example 84 Ethyl8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate

To a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate(Reference Example 83) (500 mg, 2.33 mmol) in tetrahydrofuran (7.8 mL),0.5 M potassium bis(trimethylsilyl)amide (solution in toluene, 4.67 mL,2.33 mmol) was added at −78° C., and the obtained solution was stirredfor 20 minutes. Thereafter, benzylchloromethylether (0.379 mL, 2.45mmol) was added, and the obtained solution was stirred at −78° C. for 30minutes and at room temperature for 1.5 hours. Saturated aqueousammonium chloride solution was added to the reaction solution, and theresulting solution was extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. To the residue, 3 M aqueous sodium hydroxide solution (1.0 mL)was added, and the obtained solution was stirred for 4 hours. Thereaction solution was extracted with ether and the organic layer waswashed with brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(279 mg, 0.834 mmol, 36%) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) δ: 1.24 (3H, t, J=7.2 Hz), 1.52-1.68 (6H, m),2.16-2.23 (2H, m), 3.46 (2H, s), 3.88-3.96 (4H, m), 4.17 (2H, q, J=7.2Hz), 4.49 (2H, s), 7.25-7.39 (5H, m).

ESI-MS: m/z=335 (M+H)⁺

Reference Example 85(8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)methanol

To a solution of ethyl8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (ReferenceExample 84) (279 mg, 0.834 mmol) in tetrahydrofuran (4.2 mL), lithiumborohydride (91.0 mg, 4.17 mmol) was added with stirring underice-cooling, and the obtained solution was stirred at 70° C. for 4hours. The reaction was quenched by adding saturated aqueous ammoniumchloride solution to the reaction solution, and the resulting solutionwas extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(183 mg, 0.625 mmol, 75%) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) δ: 1.48-1.66 (8H, m), 2.76 (1H, t, J=6.0 Hz),3.43 (2H, s), 3.60 (2H, d, J=6.0 Hz), 3.91-3.95 (4H, m), 4.52 (2H, s),7.27-7.38 (5H, m).

ESI-MS: m/z=293 (M+H)⁺

Reference Example 868-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carbaldehyde

To a solution of(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)methanol (ReferenceExample 85) (183 mg, 0.625 mmol) in dimethyl sulfoxide (2.1 mL), 50%sulfur trioxide-pyridine complex (596 mg, 1.87 mmol) and triethylamine(0.522 mL, 3.75 mmol) were added, and the obtained solution was stirredat room temperature for 20 minutes. The reaction was quenched by addingwater to the reaction solution, and the resulting solution was extractedwith ethyl acetate. The organic layer was washed sequentially with 20%aqueous citric acid solution, saturated sodium bicarbonate solution andbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(172 mg, 0.592 mmol, 95%) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) δ: 1.55-1.67 (6H, m), 2.03-2.11 (2H, m), 3.45(2H, s), 3.90-3.95 (4H, m), 4.47 (2H, s), 7.25-7.36 (5H, m), 9.60 (1H,s).

ESI-MS: m/z=291 (M+H)⁺

Reference Example 878-(Benzyloxymethyl)-8-ethynyl-1,4-dioxaspiro[4.5]decane

To a solution of8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (ReferenceExample 86) (100 mg, 0.344 mmol) in methanol (5.2 mL), potassiumcarbonate (143 mg, 1.03 mmol) anddimethyl-1-diazo-2-oxopropylphosphonate (165 mg, 0.861 mmol) were addedwith stirring under ice-cooling, and the obtained solution was stirredat room temperature for 1 hour. The reaction was quenched by addingwater to the reaction solution, and the resulting solution was extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the captioned compound (88.9 mg, 0.310 mmol, 90%) asa colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) δ: 1.52-1.71 (4H, m), 1.77-1.85 (2H, m),1.94-2.04 (2H, m), 2.19 (1H, s), 3.38 (2H, s), 3.89-3.99 (4H, s), 4.61(2H, s), 7.25-7.37 (5H, m).

ESI-MS: m/z=287 (M+H)⁺

Reference Example 883-(8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)propyn-1-ol

To a solution of 8-(benzyloxymethyl)-8-ethynyl-1,4-dioxaspiro[4.5]decane(Reference Example 87) (393 mg, 1.37 mmol) in tetrahydrofuran (4.6 mL),2.6 M n-butyllithium (solution in hexane, 0.555 mL, 1.44 mmol) was addedat −78° C., and the obtained solution was stirred for 10 minutes.Further, 4-methylbenzaldehyde (0.178 mL, 1.51 mmol) was added, and theobtained solution was allowed to warm gradually to room temperature andstirred for 1 hour. Saturated aqueous ammonium chloride solution wasadded to the reaction solution, and the resulting solution was extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the captioned compound (459 mg, 1.13 mmol, 82%) as acolorless oily compound.

¹H-NMR (400 MHz, CDCl₃) δ: 1.62-1.71 (4H, m), 1.79-1.86 (2H, m),1.92-2.02 (2H, m), 2.23 (1H, brs), 2.34 (3H, s), 3.41 (2H, s), 3.89-3.98(4H, m), 4.59 (2H, m), 5.44 (1H, d, J=5.2 Hz), 7.15 (2H, d, J=8.0 Hz),7.25-7.35 (5H, m), 7.43 (2H, d, J=8.0 Hz).

ESI-MS: m/z=407 (M+H)⁺

Reference Example 893-(8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)propyn-1-one

To a solution of3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)propyn-1-ol(Reference Example 88) (585 mg, 1.44 mmol) in dichloromethane (7.2 mL),manganese dioxide (625 mg, 7.19 mmol) was added, and the obtainedsolution was stirred at room temperature for 13 hours. The reactionsolution was filtered through Celite and the filtrate was concentratedunder reduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(540 mg, 1.33 mmol, 93%) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) δ: 1.71-1.80 (4H, m), 1.97-2.03 (4H, m), 2.41(3H, s), 3.52 (2H, s), 3.91-4.00 (4H, m), 4.63 (2H, m), 7.21 (2H, d,J=8.0 Hz), 7.25-7.38 (5H, m), 8.03 (2H, d, J=8.0 Hz).

ESI-MS: m/z=405 (M+H)⁺

Reference Example 903-(8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazole

To a solution of 4-methoxyphenylhydrazine hydrochloride (280 mg, 1.60mmol) in ethanol (2.7 mL), triethylamine (0.447 mL, 3.20 mmol) was addeddropwise, and the obtained solution was stirred at room temperature for30 minutes. To the reaction solution, a solution of3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)propyn-1-one(Reference Example 89) (540 mg, 1.33 mmol) in ethanol (2.7 mL) was addeddropwise, and the obtained solution was stirred at room temperature for14 hours. Thereafter, the reaction solution was concentrated underreduced pressure. Water was added to the residue and the resultant wasextracted with ethyl acetate. The organic layer was washed with 1 Mhydrochloric acid, distilled water and brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the captioned compound (458 mg, 0.872 mmol, 65%) as awhite amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.64-1.72 (2H, m), 1.76-1.85 (2H, m),1.89-1.98 (2H, m), 2.27-2.35 (5H, m), 3.50 (2H, s), 3.80 (3H, s),3.90-3.99 (4H, m), 4.49 (2H, s), 6.38 (1H, s), 6.80-6.85 (2H, m),7.06-7.31 (11H, m).

ESI-MS: m/z=525 (M+H)⁺

Reference Example 914-(Benzyloxymethyl)-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-1-one

To a solution of3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazole(Reference Example 90) (458 mg, 0.872 mmol) in tetrahydrofuran (2.2 mL),6 M hydrochloric acid (4.4 mL) was added, and the obtained solution wasstirred at room temperature for 15 hours. The reaction solution wascooled in ice and 50% aqueous sodium hydroxide solution was addeddropwise thereto at 0° C. until basic. Thereafter, the resultingsolution was extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(387 mg, 0.804 mmol, 92%) as a white amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 2.11-2.21 (2H, m), 2.31-2.39 (5H, m),2.52-2.68 (4H, m), 3.57 (2H, s), 3.81 (3H, s), 4.51 (2H, s), 6.44 (1H,s), 6.83-6.88 (2H, m), 7.08-7.34 (11H, m).

ESI-MS: m/z=481 (M+H)⁺

Reference Example 928-(4,5-Bis(4-methoxyphenyl)oxazol)-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 2-chloro-1,4-bis(4-methoxyphenyl)oxazole (1.01 g, 3.20mmol), which was synthesized by the known production process (WO2007/111323), in tetrahydrofuran (32 mL), 1.09 M borane-tetrahydrofurancomplex (4.0 mL, 4.36 mmol) was added at 0° C., and the obtainedsolution was stirred at the same temperature for 1 hour. To the reactionsolution, 2.66 M n-butyllithium (1.47 mL, mmol) was added at −78° C.,and the obtained solution was stirred at the same temperature for 1hour. To the reaction solution, 1,4-cyclohexanedione monoethylene ketal(524 mg, 3.36 mmol) was added, and the obtained solution was allowed towarm gradually to room temperature with stirring. To the reactionsolution, 1 M hydrochloric acid was added to make the mixture acidic,and the resulting solution was extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(844 mg, 1.92 mmol, 60%) as a light yellow amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.71-1.80 (2H, m), 2.01-2.11 (4H, m),2.30-2.41 (2H, m), 2.76 (1H, s), 3.83 (3H, s), 3.84 (3H, s), 3.99 (4H,dd, J=Hz), 6.89 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 7.50 (2H, d,J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz).

Reference Example 93 1,4-Dioxaspiro[4.5]decane-8-carboxamide

To a solution of 1,4-dioxaspiro[4.5]decane-8-carboxylic acid (823 mg,4.42 mmol) in tetrahydrofuran (22 mL), triethylamine (5.87 mL, 42.1mmol) and n-propyl chloroformate were added at 0° C., and the obtainedsolution was stirred at the same temperature for 1 hour. After addingdropwise, the obtained solution was stirred at room temperature for 30minutes. To the reaction solution, 28% aqueous ammonia (1.5 mL) wasadded, and the obtained solution was stirred at room temperature for 1hour. The organic layer was separated from the reaction solution, driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the captioned compound (694 mg, 3.75 mmol, 85%) as acolorless amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.53-1.61 (2H, m), 1.72-1.86 (4H, m),1.91-1.98 (2H, m), 2.17-2.25 (1H, m), 3.95 (4H, s), 5.29 (1H, brs), 5.46(1H, brs).

ESI-MS: m/z=186 (M+H)⁺

Reference Example 94 1,4-Dioxaspiro[4.5]decane-8-carbothioamide

To a solution of 1,4-dioxaspiro[4.5]decane-8-carboxamide (ReferenceExample 93) (281 mg, 1.52 mmol) in toluene (5 mL), Lawson's reagent (337mg, 0.834 mmol) was added, and the obtained solution was stirred at 100°C. for 1 hour before being cooled to room temperature. Methanol wasadded to the reaction solution, and the obtained solution wasconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (147 mg, 0.730 mmol, 48%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.57-1.66 (2H, m), 1.79-1.90 (4H, m),1.97-2.03 (2H, m), 2.64-2.72 (1H, m), 3.96 (4H, s), 6.89 (1H, brs), 7.46(1H, brs).

ESI-MS: m/z=202 (M+H)⁺

Reference Example 958-(4-(4-Methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decane

A solution of 1,4-dioxaspiro[4.5]decane-8-carbothioamide (ReferenceExample 94) (389 mg, 1.93 mmol) and2-bromo-1-(4-methoxyphenyl)-2-(p-tolyl)ethanone (588 mg, 1.84 mmol) inacetonitrile (9.2 mL) was stirred at room temperature for 4 hours.Saturated aqueous sodium hydrogen carbonate solution was added to thereaction solution, and the resulting solution was extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the captioned compound (630 mg, 1.49 mmol, 81%) as a colorlessamorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.68-1.76 (2H, m), 1.88-1.98 (4H, m),2.18-2.24 (2H, m), 2.35 (3H, s), 3.05-3.13 (1H, m), 180 (3H, s), 3.99(4H, s), 6.79-6.82 (2H, m), 7.11 (2H, d, J=8.0 Hz), 7.22 (2H, d, J=8.0Hz), 7.43-7.46 (2H, m).

ESI-MS: m/z=422 (M+H)⁺

Reference Example 968-(4-(4-Methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of8-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decane(Reference Example 95) (734 mg, 1.74 mmol) in tetrahydrofuran (8.7 mL),1.63 M n-butyllithium/solution in n-hexane (1.17 mL) was added at −78°C., and the obtained solution was stirred at the same temperature for 1hour. The reaction solution was added at −78° C. to a solution of3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (546 mg, 2.09 mmol) intetrahydrofuran (8.7 mL), and the obtained solution was allowed to warmgradually to room temperature with stirring. Distilled water was addedto the reaction solution, and the resulting solution was extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the captioned compound (417 mg, 0.954 mmol, 55%) as a colorlessamorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.73-1.79 (2H, m), 2.03-2.10 (4H, m),2.32-2.39 (2H, m), 2.37 (3H, s), 2.78 (1H, s), 3.84 (3H, s), 3.97-4.02(4H, m), 6.88-6.92 (2H, m), 7.16 (2H, d, J=8.4 Hz), 7.47 (2H, d, J=8.4Hz), 7.55-7.58 (2H, m).

ESI-MS: m/z=438 (M+H)⁺

Reference Example 974-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyl2-benzyloxycarbonylamino acetate

To a solution of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexane-cis-1,4-diol(Example 2-B) (76.0 mg, 0.201 mmol) in dichloromethane (2.00 mL),triethylamine (0.084 mL, 0.60 mmol), 2-benzyloxycarbonylamino aceticacid (46.2 mg, 0.241 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.2 mg,0.241 mmol) and 1-hydroxybenzotriazole (15.4 mg, 0.100 mmol) were addedat room temperature, and the resulting solution was stirred for 20hours. Distilled water was added to the reaction solution, and theresulting solution was extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (33.2 mg, 0.058 mmol, 29%) as a colorless amorphousproduct.

¹H-NMR (400 MHz, CDCl₃) δ: 1.91-2.07 (8H, m), 2.33 (3H, s), 2.75 (1H,s), 3.80 (3H, s), 3.98-3.99 (2H, m), 4.89-4.94 (1H, m), 5.14 (2H, s),5.33-5.35 (1H, m), 6.36 (1H, s), 6.82-6.86 (2H, m), 7.08-7.10 (4H, m),7.17-7.21 (2H, m), 7.29-7.38 (5H, m).

ESI-MS: m/z=552 (M−OH)⁺

Reference Example 98(S)-4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyl2-(benzyloxycarbonylamino)-3-methylbutanoate was synthesized in the samemanner as in Reference Example 97

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (3H, d, J=6.4 Hz), 0.99 (3H, d, J=6.4Hz), 1.89-2.10 (8H, m), 2.16-2.24 (1H, m), 2.34 (3H, s), 2.63 (1H, s),3.81 (3H, s), 4.30-4.33 (1H, m), 4.88-4.95 (1H, m), 5.12 (2H, s),5.28-5.30 (1H, m), 6.36 (1H, s), 6.78-6.82 (2H, m), 7.09-7.10 (4H, m),7.18-7.24 (2H, m), 7.29-7.38 (5H, m).

ESI-MS: m/z=594 (M−OH)⁺

Reference Example 99(S)-4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexyloxy)methyl2-(benzyloxycarbonylamino)-3-methylbutanoate

To a solution of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexane-cis-1,4-diol(Example 2-B) (199 mg, 0.506 mmol) in dichloromethane (3.00 mL),molecular sieves 4A (300 mg) and diisopropyl ethylamine (0.210 mL, 1.21mmol) were added at room temperature, and the resulting solution wascooled to −50° C. Subsequently, (S)-iodomethyl2-benzyloxycarbonylamino-3-methylbutanoate (0.187 mL, 1.26 mmol) andsilver trifluoromethanesulfonate (232 mg, 0.904 mmol) were added at thesame temperature, and the obtained solution was stirred for 2 hours.Thereafter, the resulting solution was stirred at −30° C. for 14 hours.Saturated sodium bicarbonate solution was added to the reactionsolution, and the resulting solution was filtered through Celite. Thefiltrate was washed with brine, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the captioned compound (123 mg, 0.192 mmol, 64%) as acolorless amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (3H, d, J=6.4 Hz), 1.01 (3H, d, J=6.4Hz), 1.88-1.99 (6H, m), 2.02-2.09 (2H, m), 2.20-2.26 (1H, m), 2.34 (3H,s), 2.50 (1H, s), 3.66-3.72 (1H, m), 3.81 (3H, s), 4.32-4.36 (1H, m),5.12 (2H, s), 5.38 (1H, d, J=6.4 Hz), 5.50 (1H, d, J=6.4 Hz), 6.37 (1H,s), 6.83-6.87 (2H, m), 7.08-7.11 (4H, m), 7.18-7.24 (2H, m), 7.29-7.38(5H, m).

ESI-MS: m/z=624 (M−OH)⁺

Reference Example 100 Dibenzyl4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexylphosphate

To a solution of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexane-cis-1,4-diol(Example 2-B) (200 mg, 0.528 mmol) in tetrahydrofuran (2.6 mL), 55%sodium hydride (55.3 mg, 1.27 mmol) and tetrabenzylpyrophosphonate (370mg, 0.687 mmol) were sequentially added with stirring under ice-cooling,and the obtained solution was stirred at room temperature for 15 hours.The reaction solution was cooled in ice and water was added thereto. Theresulting solution was extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (251 mg, 0,393 mmol, 74%) as a colorless transparentoily compound.

¹H-NMR (400 MHz, CDCl₃) δ: 1.87-2.11 (8H, m), 2.33 (3H, s), 3.79 (3H,s), 4.42-4.51 (1H, m), 5.00-5.12 (4H, m), 6.34 (1H, s), 6.81-6.87 (2H,m), 7.09 (4H, s), 7.16-7.23 (2H, m), 7.29-7.37 (10H, m).

ESI-MS: m/z=639 (M+H)⁺

With regard to the compounds, the compounds of the following Examples 1to 71 and Comparative Examples 1 to 30 were synthesized. As thecompounds used for the syntheses of the compounds of Examples, for whicha synthesis method is not described, commercially available compoundswere used.

Example 11-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexanol

To a suspension of 4-methoxyphenylhydrazine (165 mg, 0.944 mmol) inethanol (5.0 mL), triethylamine (258 μL, 1.88 mmol) was added, and theobtained solution was stirred at room temperature for 30 minutes. Theresulting solution was added to a solution of3-(1-hydroxycyclohexyl)-1-(4-tolyl)-2-propyn-1-one (Reference Example14) (214 mg, 0.883 mmol) in ethanol (3.0 mL), and the resulting mixturewas stirred at room temperature for 20 hours. The reaction solution wasconcentrated under reduced pressure, and distilled water was added tothe residue. The resulting solution was extracted with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain the titlecompound (141 mg, 0,389 mmol, 44%) as a yellow amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.31-1.42 (1H, m), 1.54-2.03 (9H, m), 2.33(3H, s), 2.52 (1H, brs), 3.81 (3H, s), 6.40 (1H, s), 6.84 (2H, d, J=8.8Hz), 7.09 (4H, s), 7.21 (2H, d, J=8.8 Hz).

Example 21-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-trans-1,4-diol(2-A)

1-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-cis-1,4-diol(2-B)

To a solution of4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-1-one(Example 37) (8.00 g, 21.3 mmol) in methanol (200 mL), sodiumborohydride (804 mg, 21.3 mmol) was added. The obtained solution wasstirred at room temperature for 2 hours, and then poured into 1 Mhydrochloric acid. The reaction solution was extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the title compound 2-A (1.66 g, 4.39 mmol, 21%) as a white solid,and the title compound 2-B (4.85 g, 12.8 mmol, 60%) as a white solid.

2-A: ¹H-NMR (400 MHz, CDCl₃) δ: 1.36 (1H, d, J=3.6 Hz), 1.64-1.72 (2H,m), 1.77-1.83 (2H, m), 2.04-2.12 (2H, m), 2.32-2.39 (5H, m), 2.56 (1H,s), 3.81 (3H, s), 4.03-4.06 (1H, m), 6.43 (1H, s), 6.85 (2H, d, J=8.8Hz), 7.10 (4H, s), 7.21 (2H, d, J=8.8 Hz).

IR (KBr, cm⁻¹): 3344, 2929, 2875, 1740, 1516, 1443, 1369, 1251, 1032,1001, 832.

ESI-MS: m/z=379 (M+H)⁺

Mp 151-153° C.

Anal. Calcd for C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. found: C, 72.97;H, 6.92; N, 7.34.

2-B: ¹H-NMR (400 MHz, CDCl₃) δ: 1.44 (1H, s), 1.81-1.99 (6H, m),2.04-2.12 (2H, m), 2.33 (3H, s), 2.56 (1H, s), 3.70-3.77 (1H, m), 3.80(3H, s), 6.37 (1H, s), 6.85 (2H, d, J=8.8 Hz), 7.09 (4H, s), 7.20 (2H,d, J=8.8 Hz).

IR (KBr, cm⁻¹): 3303, 2918, 1517, 1442, 1366, 1248, 1063, 1026, 837,807.

ESI-MS: m/z=379 (M+H)⁺

Mp 164-166° C.

Anal. Calcd for C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. found: C, 72.87;H, 6.86; N, 7.22.

Example 31-(1-(4-Methoxyphenyl)-5-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)cyclohexan-cis-1,4-diol

To a solution of4-hydroxy-4-(1-(4-methoxyphenyl)-5-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)-cyclohexan-1-one(Example 38) (109.5 mg, 0.29 mmol) in methanol (1.5 mL), sodiumborohydride (12.1 mg, 0.32 mmol) was added. The obtained solution wasstirred at room temperature for 40 minutes, and 1 M hydrochloric acidwas then added thereto. The reaction solution was washed with ethylacetate, and the aqueous layer was basified with 1 M aqueous sodiumhydroxide solution, followed by extraction of the resulting mixturetwice with ethyl acetate. The organic layers were washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by flash chromatography (silica gel,ethyl acetate) to obtain the title compound (30.6 mg, 0.81 mmol, 28%) asa white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.59 (1H, brs), 1.81-2.00 (6H, m), 2.05-2.08(2H, m), 2.55 (3H, s), 2.61 (1H, s), 3.71-3.78 (1H, m), 3.81 (3H, s),6.46 (1H, s), 6.86 (2H, d, J=8.8 Hz), 7.06 (1H, d, J=8.0 Hz), 7.18 (2H,d, J=8.8 Hz), 7.32 (1H, dd, J=2.0, 8.0 Hz), 8.40 (1H, d, J=2.0 Hz).

IR (KBr, cm⁻¹): 3444, 2933, 2858, 1516, 1249, 1067, 968, 839.

ESI-MS: m/z=380 (M+H)⁺

Example 41-(1,5-Bis(4-methoxyphenyl)-1H-pyrazol-3-yl)cyclohexan-trans-1,4-diol(4-A)

1-(1,5-Bis(4-methoxyphenyl)-1H-pyrazol-3-yl)cyclohexan-cis-1,4-diol(4-B)

To a solution of4-(1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl)-4-hydroxy-cyclohexan-1-one(Example 39) (523 mg, 1.38 mmol) in methanol, sodium borohydride (65 mg,1.7 mmol) was added. The obtained solution was stirred at roomtemperature for 1.5 hours, and concentrated under reduced pressure.Distilled water was added to the residue, and the resulting solution wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by flash chromatography to separate into low polarcomponent and high polar component. The low polar component was purifiedby recrystallization (ethyl acetate/n-hexane=2/1) to obtain the titlecompound 4-A (79 mg, 0.20 mmol, 14%) as a white crystal. The high polarcomponent was purified by recrystallization (ethyl acetate/n-hexane=2/1)to obtain the title compound 4-B (186 mg, 0.471 mmol, 34%) as a whitecrystal.

4-A: ¹H-NMR (400 MHz, CDCl₃) δ: 1.33 (1H, d, J=3.4 Hz), 1.63-1.73 (2H,m), 1.75-1.84 (2H, m), 2.03-2.13 (2H, m), 2.30-2.39 (2H, m), 2.55 (1H,s), 3.80 (3H, s), 3.81 (3H, s), 4.02-4.08 (1H, m), 6.40 (1H, s), 6.82(2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.21(2H, d, J=8.8 Hz).

IR (KBr, cm⁻¹): 3379, 1613, 1517, 1503, 1251, 1180, 1032, 1001, 835.

ESI-MS: m/z=395 (M+H)⁺

4-B: ¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (1H, d, J=4.1 Hz), 1.79-2.55 (8H,m), 2.55 (1H, s), 3.69-3.78 (1H, m), 3.80 (3H, s), 3.81 (3H, s), 6.34(1H, s), 6.81 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 7.13 (2H, d,J=8.8 Hz), 7.20 (2H, d, J=8.8 Hz).

IR (KBr, cm⁻¹): 3385, 1613, 1517, 1503, 1250, 1064, 1031, 970, 835.

ESI-MS: m/z=395 (M+H)⁺

Example 51-(5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)cyclohexan-trans-1,4-diol(5-A)

1-(5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)cyclohexan-cis-1,4-diol(5-B)

To a solution of4-(5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-4-hydroxy-cyclohexan-1-one(Example 40) (619 mg, 1.56 mmol) in methanol (15.6 mL), sodiumborohydride (59.0 mg, 1.56 mmol) was added. The obtained solution wasstirred at room temperature for 1 hour, and then poured into 1 Mhydrochloric acid. The reaction solution was extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the title compound 5-A (131 mg, 0.328 mmol, 21%) as a whitesolid, and the title compound 5-B (291 mg, 0.730 mmol, 47%) as a whitesolid.

5-A: ¹H-NMR (400 MHz, CDCl₃) δ: 1.32 (1H, d, J=3.2 Hz), 1.63-1.73 (2H,m), 1.76-1.84 (2H, m), 2.03-2.12 (2H, m), 2.30-2.39 (2H, m), 2.50 (1H,s), 3.82 (3H, s), 4.02-4.09 (1H, m), 6.46 (1H, s), 6.84-6.87 (2H, m),7.14 (2H, d, J=8.8 Hz), 7.19 (2H, d, J=8.8 Hz), 7.26-7.28 (2H, m).

ESI-MS: m/z=399 (M+H)⁺

5-B: ¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (1H, d, J=5.2 Hz), 1.82-2.09 (8H,m), 2.49 (1H, s), 3.70-3.78 (1H, s), 3.82 (3H, s), 6.41 (1H, s),6.85-6.87 (2H, m), 7.13 (2H, d, J=8.4 Hz), 7.18 (2H, d, J=8.4 Hz),7.25-7.27 (2H, m).

ESI-MS: m/z=399 (M+H)⁺

Example 61-(1-(4-Chlorophenyl)-5-p-tolyl-1H-pyrazol-3-yl)cyclohexan-trans-1,4-diol(6-A)

1-(1-(4-Chlorophenyl)-5-p-tolyl-1H-pyrazol-3-yl)cyclohexan-cis-1,4-diol(6-B)

To a solution of4-hydroxy-4-(1-(4-chlorophenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-1-one(Example 41) (510 mg, 1.34 mmol) in methanol (13 mL), sodium borohydride(53 mg, 1.40 mmol) was added, and the obtained solution was stirred atroom temperature for 2 hours. The reaction solution was concentratedunder reduced pressure, and then dissolved into ethyl acetate, andwashed with distilled water and brine. The organic layer was dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the title compound 6-A (114 mg, 0.298 mmol, 22%) as awhite solid, and the title compound 6-B (360 mg, 0.940 mmol, 70%) as awhite solid.

6-A: ¹H-NMR (400 MHz, CDCl₃) δ: 1.36 (1H, br), 1.65-1.72 (2H, m),1.77-1.82 (2H, m), 2.04-2.11 (2H, m), 2.31-2.38 (2H, m), 2.36 (3H, s),2.51 (1H, s), 4.03-4.08 (1H, m), 6.44 (1H, s), 7.10 (2H, d, J=8.8 Hz),7.13 (2H, d, J=8.8 Hz), 7.22-7.30 (4H, m).

IR (KBr, cm⁻¹): 3349, 2918, 1497, 1440, 1366, 1240, 1098, 1007, 969,833, 810.

ESI-MS: m/z=383 (M+H)⁺

6-B: ¹H-NMR (400 MHz, CDCl₃) δ: 1.45 (1H, br), 1.80-1.99 (6H, m),2.03-2.07 (2H, m), 2.35 (3H, s), 2.51 (1H, s), 3.70-3.80 (1H, m), 6.39(1H, s), 7.09 (2H, d, J=8.4 Hz), 7.13 (2H, d, J=8.4 Hz), 7.21-7.24 (2H,m), 7.27-7.31 (2H, m).

IR (KBr, cm⁻¹): 3365, 2946, 1496, 1442, 1368, 1241, 1095, 1059, 1014,970, 887.

ESI-MS: m/z=365 (M−OH)⁺

The compounds of the following Examples were prepared by the sameprocedure as described above.

TABLE 7 Example Structural Formula Compound Data 7

¹H-NMR (400 MHz, CDCl₃) δ: 1.34 (I H, d, J = 3.2 Hz), 1.64-1.72 (2H, m),1.76-1.83 (2H, m), 2.03-2.12 (2H, m), 2.30-2.39 (2H, m), 2.45 (1H, s),4.03-4.09 (1H, m), 6.48 (1H, s), 7.15 (2H, d, J = 8.8 Hz), 7.22 (2H, d,J = 8.8 Hz), 7.30-7.33 (4H, m). ESI-MS: m/z = 403 (M + H)⁺ 8

¹H-NMR (400 MHz, CDCl₃) δ: 1.45 (1H, d, J = 4.0 Hz), 1.80-2.07 (8H, m),2.46 (1H, s), 3.70-3.79 (1H, s), 6.43 (1H, s), 7.14 (2H, d, J = 8.8 Hz),7.21 (2H, d, J = 8.8 Hz), 7.29-7.33 (4H, m). ESI-MS: m/z = 403 (M + H)⁺9

¹H-NMR (400 MHz, CDCl₃) δ: 1.33 (1H, d, J = 3.2 Hz), 1.65-1.73 (2H, m),1.78-1.84 (2H, m), 2.04-2.13 (2H, m), 2.32-2.40 (2H, m), 2.51 (1H, s),4.03-4.09 (1H, m), 6.48 (1H, s), 7.14-7.16 (2H, m), 7.26-7.28 (7H, m).ESI-MS: m/z = 369 (M + H)⁺ 10

¹H-NMR (400 MHz, CDCl₃) δ: 1.43 (1H, d, J = 5.2 Hz), 1.81-2.09 (8H, m),2.50 (1H, s), 3.71-3.79 (1H, m), 6.43 (1H, s), 7.12-7.16 (2H, m),7.25-7.38 (7H, m). ESI-MS: m/z = 369 (M + H)⁺ 11

¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (1H, brs), 1.64-1.72 (2H, m), 1.77-1.83(2H, m), 2.04-2.11 (2H, m), 2.31-2.38 (2H, m), 2.34 (3H, s), 2.35 (3H,s), 2.59 (1H, s), 4.02-4.07 (1H, m), 6.43 (1H, s), 7.09-7.11 (4H, m),7.12 (2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz). IR (KBr, cm⁻¹):3343, 2918, 1518, 1440, 1367, 1266, 1240, 1196, 1159, 1107, 1007, 824,810. ESI-MS: m/z = 363 (M + H)⁺ 12

¹H-NMR (400 MHz, CDCl₃) δ: 1.48 (1H, brs), 1.80-1.99 (6H, m), 2.02-2.09(2H, m), 2.34 (3H, s), 2.35 (3H, s), 2.61 (1H, s), 3.70-3.78 (1H, m),6.38 (1H, s), 7.08-7.12 (4H, m), 7.12 (2H, d, J = 8.8 Hz), 7.17 (2H, d,J = 8.8 Hz). IR (KBr, cm⁻¹): 3375, 2937, 2870, 1519, 1502, 1440, 1362,1217, 1193, 1112, 1064, 1042, 1017, 973, 886, 821, 804. ESI-MS: m/z =345 (M − OH)⁺ 13

¹H-NMR (400 MHz, CDCl₃) δ: 1.47 (1H, brs), 1.64-1.73 (2H, m), 1.76-1.85(2H, m), 2.03-2.12 (2H, m), 2.31-2.40 (2H, m), 2.34 (3H, s), 2.62 (1H,s), 4.02-4.08 (1H, m), 6.45 (1H, s), 7.08-7.14 (4H, m), 7.26-7.36 (5H,m). IR (KBr, cm⁻¹): 3337, 2920, 1599, 1506, 1437, 1366, 1005, 810, 765,696. ESI-MS: m/z = 349 (M + H)⁺ 14

¹H-NMR (400 MHz, CDCl₃) δ: 1.50 (1H, brs), 1.80-2.00 (6H, m), 2.03-2.09(2H, m), 2.34 (3H, s), 2.60 (1H, s), 3.70-3.79 (1H, m), 6.40 (1H, s),7.08-7.12 (4H, m), 7.27-7.35 (5H, m). IR (KBr, cm⁻¹): 3374, 2919, 1596,1505, 1440, 1361, 1217, 1112, 1064, 1044, 1019, 973, 886, 819, 799, 771,693. ESI-MS: m/z = 331 (M − OH)⁺ 15

¹H-NMR (400 MHz, CDCl₃) δ: 1.42 (1H, d, J = 4.8 Hz), 1.79-2.01 (6H, m),2.03-2.08 (2H, m), 2.54 (1H, s), 3.71-3.80 (1H, m), 3.81 (3H, s), 6.41(1H, s), 6.84 (2H, d, J = 6.8 Hz), 7.18-7.23 (4H, m), 7.28-7.30 (3H, m).ESI-MS: m/z = 365 (M + H)⁺ 16

¹H-NMR (400 MHz, CDCl₃) δ: 1.34 (1H, d, J = 3.6 Hz), 1.65-1.73 (2H, m),1.17-1.85 (2H, m), 2.03-2.12 (2H, m), 2.32-2.40 (2H, m), 2.54 (1H, s),3.81 (3H, s), 4.00-4.10 (1H, m), 6.46 (1H, s), 6.85 (2H, d, J = 8.8 Hz),7.19-7.24 (4H, m), 7.28-7.31 (3H, m). ESI-MS: m/z = 365 (M + H)⁺ 17

¹H-NMR (400 MHz, CDCl₃) δ: 1.34 (1H, d, J = 3.6 Hz), 1.62-1.73 (2H, m),1.77-1.85 (2H, m), 2.03-2.12 (2H, m), 2.31-2.40 (5H, m), 2.57 (1H, s),4.00-4.08 (1H, m), 6.61 (1H, s), 7.12 (2H, d, J = 8.4 Hz), 7.17 (2H, d,J = 8.8 Hz), 7.21-7.24 (2H, m), 7.28-7.30 (3H, m). ESI-MS: m/z = 349(M + H)⁺ 18

¹H-NMR (400 MHz, CDCl₃) δ: 1.79-2.00 (6H, m), 2.03-2.08 (2H, m), 2.34(3H, s), 2.57 (1H, s), 3.70-3.79 (1H, m), 6.41 (1H, s), 7.10 (2H, d, J =8.4 Hz), 7.16 (2H, d, J = 8.4 Hz), 7.27-7.31 (3H, m), 7.19-7.23 (2H, m).ESI-MS: m/z = 349 (M + H)⁺ 19

¹H-NMR (400 MHz, CDCl₃) δ: 1.35 (1H, d, J = 3.6 Hz), 1.62-1.73 (2H, m),1.75-1.86 (2H, m), 2.02-2.13 (2H, m), 2.29-2.40 (5H, m), 2.58 (1H, s),180 (3H, s), 4.01-4.09 (1H, m), 6.40 (1H, s), 6.82 (2H, d, J = 8.8 Hz),7.10-7.20 (6H, m). 20

¹H-NMR (400 MHz, CDCl₃) δ: 1.34 (1H, d, J = 5.6 Hz), 1.80-2.10 (8H, m),2.34 (3H, s), 2.59 (1H, s), 3.68-3.79 (1H, m), 3.80 (3H, s), 6.34 (1H,s), 6.81 (2H, d, J = 8.4 Hz), 7.08-7.20 (6H, m). 21

¹H-NMR (400 MHz, CDCl₃) δ: 1.48(1H, s), 1.62-1.72 (2H, m), 1.73-1.83(2H, m), 2.02-2.12 (2H, m), 2.30-2.39 (2H, m), 2.57 (1H, s), 3.82 (3H,s), 4.02-4.06 (1H, m), 6.42 (1H, s), 6.84 (2H, d, J = 8.8 Hz), 7.13 (2H,d, J = 12.0 Hz), 7.23 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.8 Hz).ESI-MS: m/z = 399 (M + H)⁺ 22

¹H-NMR (400 MHz, CDCl₃) δ: 1.79-1.99 (6H, m), 2.03-2.07 (3H, m),3.70-3.79 (1H, m), 3.81 (3H, s), 6.37 (1H, s), 6.84 (2H, d, J = 8.8 Hz),7.14 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.8Hz). ESI-MS: m/z = 399 (M + H)⁺ 23

¹H-NMR (400 MHz, CDCl₃) δ: 1.38(1H, s), 1.64-1.74 (2H, m), 1.76-1.85(2H, m), 2.03-2.13 (2H, m), 2.31-2.40 (2H, m), 2.58 (1H, s), 3.81 (3H,s), 4.06 (1H, s), 6.42 (1H, s), 6.82 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J= 8.8 Hz), 7.28-7.37 (5H, m). ESI-MS: m/z = 365 (M + H)⁺ 24

¹H-NMR (400 MHz, CDCl₃) δ: 1.47 (1H, s), 1.79-1.99 (6H, m), 2.03-2.07(2H, m), 2.59 (1H, s), 3.70-3.79 (1H, m), 3.80 (3H, s), 6.37 (1H, s),6.82 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.27-7.36 (5H, m).ESI-MS: m/z = 365 (M + H)⁺ 25

¹H-NMR (400 MHz, CDCl3) δ: 1.35 (1H, s), 1.67-1.71 (2H, m), 1.78-1.84(2H, m), 2.0-2.11 (2H, m), 2.33-2.40 (2H, m), 2.49 (1H, s), 3.83 (3H,s), 4.07 (1H, m), 6.53 (1H, s), 6.87 (2H, d, J = 8.2 Hz), 7.19 (2H, d, J= 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.55 (2H, d, J = 8.2 Hz). ESI-MS:m/z = 433 (M + H)⁺ 26

¹H-NMR (400 MHz, CDCl3) δ: 1.44 (1H, d, J = 4.0 Hz), 1.84-2.01 (8H, m),2.48 (1H, s), 3.75 (1H, s), 3.82 (3H, s), 6.49 (1H, s), 6.87 (2H, d, J =9.2 Hz), 7.19 (2H, d, J = 9.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.55 (2H,d, J = 8.2 Hz). ESI-MS: m/z = 433 (M + H)⁺ 27

¹H-NMR (400 MHz, CDCl3) δ: 1.23 (3H, t, J = 7.6 Hz), 1.33 (1H, br),1.64-1.73 (2H, m), 1.77-1.84 (2H, m), 2.03-2.12 (2H, m), 2.31-2.40 (2H,m), 2.55 (1H, s), 2.63 (2H, q, J = 7.6 Hz), 3.81 (3H, s), 4.02-4.07 (1H,m), 6.43 (1H, s), 6.83-6.89 (2H, m), 7.12 (4H, s), 7.19-7.28 (2H, m).ESI-MS: m/z = 393 (M + H)⁺ 28

¹H-NMR (400 MHz, CDCl3) δ: 1.23 (3H, t, J = 7.6 Hz), 1.41 (1H, d, J =4.4 Hz), 1.80-2.09 (8H, m), 2.55 (1H, s), 2.63 (2H, q, J = 7.6 Hz),3.69-3.83 (4H, m), 6.38 (1H, s), 6.82-6.87 (2H, m), 7.12 (4H, s),7.17-7.28 (2H, m), ESI-MS: m/z = 393 (M + H)⁺ 29

¹H-NMR (400 MHz, CDCl₃) δ: 1.32 (1H, br), 1.65-1.72 (2H, m), 1.77-1.83(2H, m), 2.04-2.11 (2H, m), 2.30-2.39 (5H, m), 2.48 (1H, br), 3.89 (3H,s), 4.02-4.08 (1H, m), 6.43 (1H, s), 6.88 (1H, t, J = 8.8 Hz), 6.93-7.02(1H, m), 7.08-7.15 (5H, m). ESI-MS: m/z = 397 (M + H)⁺ 30

¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (1H, br), 1.80-2.08 (8H, m), 2.35 (3H,s), 2.48 (1H, s), 3.70-3.80 (1H, m), 3.89 (3H, s), 6.38 (1H, s), 6.88(1H, t, J = 8.8 Hz), 6.96-7.01 (1H, m), 7.06-7.14 (5H, m). ESI-MS: m/z =397 (M + H)⁺ 31

¹H-NMR (400 MHz, CDCl₃) δ: 1.63-1.84 (4H, m), 2.03-2.12 (2H, m), 2.26(3H, d, J = 1.6 Hz), 231-2.41 (2H, m), 2.51 (1H, br), 3.82 (3H, s),4.03-4.08 (1H, m), 6.44 (1H, s), 6.84-6.90 (4H, m), 7.08 (1H, t, J = 8.0Hz), 7.18-7.23 (2H, m). ESI-MS: m/z = 397 (M + H)⁺ 32

¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (1H, d, J = 4.8 Hz), 1.81-2.08 (8H, m),2.25 (3H, d, J = 1.6 Hz), 2.51 (1H, s), 3.69-3.78 (1H, m), 3.82 (3H, s),6.39 (1H, s), 6.84-6.89 (4H, m), 7.09 (1H, t, J = 7.6 Hz), 7.17-7.24(2H, m). ESI-MS: m/z = 397 (M + H)⁺ 33

¹H-NMR (400 MHz, CDCl₃) δ: 1.32 (1H, br), 1.65-1.72 (2H, m), 1.77-1.83(2H, m), 2.04-2.11 (2H, m), 2.30-2.39 (5H, m), 2.48 (1H, br), 3.89 (3H,s), 4.02-4.08 (1H, m), 6.43 (1H, s), 6.88 (1H, t, J = 8.8 Hz), 6.93-7.02(1H, m), 7.08-7.15 (5H, m). ESI-MS: m/z = 397 (M + H)⁺ 34

¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (1H, br), 1.80-2.08 (8H, m), 2.35 (3H,s), 2.48 (1H, s), 3.70-3.80 (1H, m), 3.89 (3H, s), 6.38 (1H, s), 6.88(1H, t, J = 8.8 Hz), 6.96-7.01 (1H, m), 7.06-7.14 (5H, m). ESI-MS: m/z =397 (M + H)⁺ 35

¹H-NMR (400 MHz, CDCl₃) δ: 1.63-1.84 (4H, m), 2.03-2.12 (2H, m), 2.26(3H, d, J = 1.6 Hz), 2.31-2.41 (2H, m), 2.51 (1H, br), 3.82 (3H, s),4.03-4.08 (1H, m), 6.44 (1H, s), 6.84-6.90 (4H, m), 7.08 (1H, t, J = 8.0Hz), 7.18-7.23 (2H, m). ESI-MS: m/z = 397 (M + H)⁺ 36

¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (1H, d, J = 4.8 Hz), 1.81-2.08 (8H, m),2.25 (3H, d, J = 1.6 Hz), 2.51 (1H, s), 3.69-3.78 (1H, m), 3.82 (3H, s),639 (1H, s), 6.84-6.89 (4H, m), 7.09 (1H, t, J = 7.6 Hz), 7.17-7.24 (2H,m). ESI-MS: m/z = 397 (M + H)⁺

Example 374-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-1-one

To a solution of8-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol(Reference Example 30) (14.6 g, 34.7 mmol) in tetrahydrofuran (69.4 mL),6 M hydrochloric acid (138.9 mL) was added, and the obtained solutionwas stirred at room temperature for 15 hours. The reaction solution wascooled in ice, and 50% aqueous sodium hydroxide solution was addeddropwise thereto at 0° C. until it became basic. Thereafter, theresulting solution was extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified byrecrystallization (n-hexane/ethyl acetate, 70° C.) to obtain the titlecompound (10.5 g, 27.9 mmol, 80%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.33-2.43 (9H, m), 2.87-2.95 (3H, m), 3.82(3H, s), 6.39 (1H, s), 6.86 (2H, d, J=8.8 Hz), 7.10 (4H, s), 7.22 (2H,d, J=8.8 Hz).

IR (KBr, cm⁻¹): 3321, 2929, 1712, 1518, 1463, 1299, 1249, 1179, 1114,1027, 961, 821.

ESI-MS: m/z=377 (M+H)⁺

Example 384-Hydroxy-4-(1-(4-methoxyphenyl)-5-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)-cyclohexan-1-one

To a solution of8-(1-(4-methoxyphenyl)-5-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol(Reference Example 31) (128.8 mg, 0.30 mmol) in tetrahydrofuran (0.6mL), 6 M hydrochloric acid (1.2 mL) was added, and the obtained solutionwas stirred at room temperature for 3 hours. The reaction solution wascooled in ice, and 50% aqueous sodium hydroxide solution was addeddropwise thereto at 0° C. until it became basic. Thereafter, theresulting solution was extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain the titlecompound (109.5 mg, 0.29 mmol, 96%) as an amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 2.34-2.44 (6H, m), 2.55 (3H, s), 2.87-2.95(2H, m), 3.18 (1H, s), 3.82 (3H, s), 6.49 (1H, s), 6.87 (2H, d, J=8.8Hz), 7.08 (1H, d, J=8.1 Hz), 7.19 (2H, d, J=8.8 Hz), 7.35 (1H, dd,J=2.2, 8.1 Hz), 8.40 (1H, d, J=2.2 Hz).

ESI-MS: m/z=378 (M+H)⁺

Example 394-(1,5-Bis(4-methoxyphenyl)-1H-pyrazol-3-yl)-4-hydroxy-cyclohexan-1-one

To a solution of8-(1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol(Reference Example 32) (658 mg, 1.50 mmol) in tetrahydrofuran (3.75 mL),6 M hydrochloric acid (7.5 mL) was added at 0° C., and the obtainedsolution was stirred at room temperature for 5 hours. The reactionsolution was neutralized by pouring it into ice-cooled 10% aqueoussodium hydroxide solution. The resulting solution was basified byaddition of saturated sodium bicarbonate solution, and extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the title compound (523 mg, 1.33 mmol, 89%) as an amorphousproduct.

¹H-NMR (400 MHz, CDCl₃) δ: 2.30-2.45 (6H, m), 2.86-2.96 (2H, m), 2.99(1H, s), 3.80 (3H, s), 3.82 (3H, s), 6.36 (1H, s), 6.82 (2H, d, J=8.8Hz), 6.87 (2H, d, J=8.8 Hz), 7.13 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8Hz).

ESI-MS: m/z=393 (M+H)⁺

Example 404-(5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-4-hydroxy-cyclohexan-1-one

To a solution of8-(5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol(Reference Example 33) (756 mg, 1.71 mmol) in tetrahydrofuran (4.3 mL),6 M hydrochloric acid (8.6 mL) was added, and the obtained solution wasstirred at room temperature for 15 hours. The reaction solution wascooled in ice, and 50% aqueous sodium hydroxide solution was addeddropwise thereto at 0° C. until it became basic. Thereafter, theresulting solution was extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain the titlecompound (619 mg, 1.56 mmol, 91%) as an amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 2.31-2.45 (6H, m), 2.85-2.98 (3H, m), 3.82(3H, s), 6.43 (1H, s), 6.86-6.90 (2H, m), 7.14 (2H, d, J=8.8 Hz), 7.19(2H, d, J=8.8 Hz), 7.26-7.29 (2H, m).

ESI-MS: m/z=397 (M+H)⁺

Example 414-Hydroxy-4-(1-(4-chlorophenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-1-one

To a solution of8-(1-(4-chlorophenyl)-5-p-tolyl-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol(Reference Example 34) (931 mg, 2.19 mmol) in tetrahydrofuran (5.5 mL),6 M hydrochloric acid (11 mL) was added, and the obtained solution wasstirred at room temperature for 15 hours. The reaction solution wasbasified by pouring it into saturated aqueous sodium hydrogen carbonatesolution, and the resulting solution was extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the title compound (513 mg, 1.35 mmol, 61%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.36 (4H, m), 2.36 (3H, s), 2.38-2.44(2H, m), 2.87-2.95 (2H, m), 2.90 (1H, s), 6.41 (1H, s), 7.10 (2H, d,J=8.0 Hz), 7.14 (2H, d, J=8.0 Hz), 7.23 (2H, d, J=8.8 Hz), 7.31 (2H, d,J=8.8 Hz).

ESI-MS: m/z=381 (M+H)⁺

The following compounds were prepared by the same procedure as describedabove.

TABLE 8 Example Structural Formula Compound Data 42

¹H-NMR (400 MHz, CDCl₃) δ: 2.31-2.45 (6H, m), 2.86-2.96 (3H, m), 6.45(1H, s), 7.15 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.31-7.35(4H, m). ESI-MS: m/z = 401 (M + H)⁺ 43

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.44 (6H, m), 2.85-2.95 (2H, m), 3.10(1H, brs), 6.45 (1H, s), 7.13-7.16 (2H, m), 7.26-7.39 (7H, m). ESI-MS:m/z = 367 (M + H)⁺ 44

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.45 (6H, m), 2.34 (3H, s), 2.36 (3H,s), 2.87-2.95 (2H, m), 2.98 (1H, s), 637 (1H, s), 7.10-7.19 (8H, m).ESI-MS: m/z = 361 (M + H)⁺ 45

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.45 (6H, m), 2.35 (3H, s), 2.87-2.96(2H, m), 2.97 (1H, s), 6.41 (1H, s), 7.09-7.13 (4H, m), 7.27-7.37 (5H,m). ESI-MS: m/z = 347 (M + H)⁺ 46

¹H-NMR (400 MHz, CD₃OD) δ: 2.44-2.38 (6H, m), 2.87-2.96 (3H, m), 3.82(3H, s), 6.43 (1H, s), 6.86 (2H, d, J = 9.0 Hz), 7.19-7.24 (4H, m),7.29-7.32 (3H, m). ESI-MS: m/z = 363 (M + H)⁺ 47

¹H-NMR (400 MHz, CDCl₃) δ: 232-2.44 (2H, m), 2.35-2.39 (5H, m),2.43-2.50 (2H, m), 2.89-2.96 (2H, m), 6.43 (1H, s), 7.13 (2H, d, J = 8.8Hz), 7.17 (2H, d, J = 8.8 Hz), 7.20-7.24 (2H, m), 7.29-7.32 (3H, m).ESI-MS: m/z = 347 (M + H)⁺ 48

¹H-NMR (400 MHz, CDCl3) δ: 2.31-2.34 (2H, m), 2.36 (3H, s), 2.37-2.39(2H, m), 2.41-2.43 (2H, m), 2.86-2.96 (2H, m), 2.99 (1H, s), 3.80 (3H,s), 6.36 (1H, s), 6.83 (2H, d, J = 8.8 Hz), 7.13-7.19 (6H, m). ESI-MS:m/z = 377 (M + H)⁺ 49

¹H-NMR (400 MHz, CDCl3) δ: 2.31-2.35 (4H, m), 2.38-2.43 (2H, m),2.86-2.96 (3H, m), 3.82 (3H, s), 6.38 (1H, s), 6.84 (2H, d, J = 9.0 Hz),7.13 (2H, d, J = 11.7 Hz), 7.23 (2H, t, J = 8.9 Hz), 7.31 (2H, d, J =11.5 Hz). ESI-MS: m/z = 397 (M + H)⁺ 50

¹H-NMR (400 MHz, CDCl3) δ: 2.31-2.45 (6H, m), 2.86-2.96 (2H, m), 3.02(1H, s), 3.80 (3H, s), 6.37 (1H, s), 6.83 (2H, d, J = 8.8 Hz), 7.14 (2H,d, J = 8.8 Hz), 7.28-7.37 (5H, m). 51

¹H-NMR (400 MHz, CDCl3) δ: 233-137 (4H, m), 2.39-2.43 (2H, m), 2.87-2.95(3H, m), 183 (3H, s), 6.50 (1H, s), 6.89 (2H, d, J = 8.0 Hz), 7.20 (2H,d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.56 (2H, d, J = 8.0 Hz).ESI-MS: m/z = 431 (M + H)⁺ 52

¹H-NMR (400 MHz, CDCl3) δ: 1.23 (3H, t, J = 7.6 Hz), 2.31-2.45 (6H, m),2.64 (2H, q, J = 7.6 Hz), 2.86-2.96 (3H, m), 3.82 (3H, s), 6.39 (1H, s),6.83-6.89 (2H, m), 7.13 (4H, s), 7.20-7.25 (2H, m). ESI-MS: m/z = 391(M + H)⁺ 53

¹H-NMR (400 MHz, CDCl₃) δ: 2.31-2.45 (9H, m), 2.86-2.97 (3H, m), 3.90(3H, s), 6.39 (1H, s), 6.89 (1H, t, J = 8.8 Hz), 6.98-7.01 (1H, m),7.08-7.15 (5H, m). ESI-MS: m/z = 395 (M + H)⁺ 54

¹H-NMR (400 MHz, CDCl₃) δ: 2.26 (3H, d, J = 1.6 Hz), 2.31-2.45 (6H, m),2.85-2.96 (3H, m), 3.82 (3H, s), 6.41 (1H, s), 6.84-6.90 (4H, m), 7.10(1H, t, J = 8.0 Hz), 7.18-7.23 (2H, m). ESI-MS: m/z = 395 (M + H)⁺ 55

¹H-NMR (400 MHz, CDCl₃) δ: 2.30-2.45 (9H, m), 183 (1H, s), 2.86-2.97(2H, m), 6.45 (1H, s), 7.10-7.20 (4H, m), 7.40-7.45 (2H, m), 7.59-7.64(2H, m). ESI-MS: m/z = 372 (M + H)⁺ 56

¹H-NMR (400 MHz, CDCl₃) δ: 2.31-2.46 (6H, m), 2.84-2.96 (3H, m), 3.83(3H, s), 6.53 (1H, s), 6.87-6.92 (2H, m), 7.15-7.21 (2H, m), 730-7.34(2H, m), 7.57-7.61 (2H, m). ESI-MS: m/z = 425 (M + H)⁺

Example 57c-4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-ylacetate

To a suspension of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-cis-1,4-diol(Example 2-B) (500 mg, 1.32 mmol) in dichloromethane (4.4 mL), aceticanhydride (0.312 mL, 3.30 mmol), pyridine (0.267 mL, 3.30 mmol), and4-dimethylaminopyridine (16.1 mg, 0.132 mmol) were added, and theobtained solution was stirred at room temperature for 45 minutes. Waterwas added to the reaction solution to quench the reaction, and theresulting solution was extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, n-hexane/ethyl acetate) to obtain the titlecompound (556 mg, 1.32 mmol, quant.) as an amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.89-2.08 (11H, m), 2.34 (3H, s), 2.64 (1H,brs), 3.81 (3H, s), 4.80-4.88 (1H, m), 6.36 (1H, s), 6.85 (2H, d, J=8.8Hz), 7.00 (4H, s), 7.20 (2H, d, J=8.8 Hz).

ESI-MS: m/z=421 (M+H)⁺

Example 584-(4-Chloro-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-c-4-hydroxy-cyclohexan-r-1-ylacetate

To a solution ofc-4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-ylacetate (Example 57) (140 mg, 0.333 mmol) in acetonitrile (1.66 mL),N-chlorosuccinimide (49 mg, 0.366 mmol) was added. The obtained solutionwas stirred at 80° C. for 15 hours, and cooled to room temperature.Brine was added to the reaction solution, and the resulting solution wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the title compound (67 mg, 0.147 mmol, 44%) as awhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.92-2.04 (6H, m), 2.28-2.36 (8H, m), 3.10(1H, s), 3.79 (3H, s), 4.85-4.88 (1H, m), 6.80-6.82 (2H, m), 7.11-7.16(6H, m).

Example 591-(4-Chloro-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-cis-1,4-diol

To a solution of4-(4-chloro-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-c-4-hydroxy-cyclohexan-r-1-ylacetate (Example 58) (67 mg, 0,147 mmol) in methanol (1.5 mL), potassiumcarbonate (102 mg, 0.736 mmol) was added, and the obtained solution wasstirred at room temperature for 2 hours. Water was added to the reactionsolution to quench the reaction, and the resulting solution wasextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by flash chromatography (silica gel,n-hexane/ethyl acetate) to obtain the title compound (58 mg, 0.140 mmol,95%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.45 (1H, s), 1.83-2.05 (6H, m), 2.21-2.23(2H, m), 2.36 (3H, s), 3.04 (1H, s), 3.76-3.79 (4H, m), 6.79-6.83 (2H,m), 7.11-7.16 (6H, m).

ESI-MS: m/z=395, 397 (M−OH)⁺

Example 60t-4-Fluoro-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-ol

To a solution ofc-4-hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cyclohexan-r-1-ylacetate (Example 57) (100 mg, 0.238 mmol) in dichloromethane (1.19 mL),Deoxofluor™ (48 μL, 0.262 mmol) was added, and the obtained solution wasstirred at room temperature for 15 minutes. To the reaction solution, 1M hydrochloric acid was added, and the resulting solution was extractedwith chloroform. The organic layer was washed with brine, and then driedover anhydrous magnesium sulfate, and concentrated under reducedpressure to obtain the residue.

To a solution of the obtained residue in methanol (2.4 mL), potassiumcarbonate (164 mg, 1.18 mmol) was added, and the obtained solution wasstirred at room temperature for 2 hours. Water was added to the reactionsolution to quench the reaction, and the resulting solution wasextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by flash chromatography (silica gel,n-hexane/ethyl acetate) to obtain the title compound (22.4 mg, 0.058mmol, 25%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.37 (1H, m), 1.72-1.77 (2H, m), 2.02-2.14(4H, m), 2.34 (3H, s), 2.38-2.49 (2H, m), 3.81 (3H, s), 4.11 (1H, m),6.52 (1H, m), 6.84 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.26 (4H,s).

ESI-MS: m/z=381 (M+H)⁺

Example 614,4-Difluoro-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexanol

To a solution of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-4-oxo-cyclohexan-1-ylacetate (Reference Example 81) (110 mg, 0.263 mmol) in dichloromethane(2.63 mL), (dimethylamino)sulfur trifluoride (DAST) (104 μL, 0.578 mmol)was added, and the obtained solution was stirred at room temperature for2 hours. To the reaction solution, 1 M hydrochloric acid was added, andthe resulting solution was extracted with chloroform. The organic layerwas washed with brine, and then dried over anhydrous magnesium sulfate,and concentrated under reduced pressure to obtain the residue.

To a solution of the obtained residue in tetrahydrofuran (193 μL) andmethanol (386 μL), 4 M aqueous sodium hydroxide solution (193 μL, 0.772mmol) was added, and the obtained solution was stirred at roomtemperature for 6 hours. Water was added to the reaction solution toquench the reaction, and the resulting solution was extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the title compound (41.0 mg, 0.103 mmol, 39%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.01-2.31 (8H, m), 2.34 (3H, s), 2.77 (1H,s), 3.81 (3H, s), 6.37 (1H, s), 6.86 (2H, d, J=8.8 Hz), 7.10 (4H, s),7.21 (2H, d, J=8.8 Hz).

ESI-MS: m/z=399 (M+H)⁺

Example 621-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-4-(trifluoromethyl)cyclohexan-cis-1,4-diol

To a solution of4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexanone(Example 37) (620 mg, 1.65 mmol) in tetrahydrofuran (6.60 mL),(trifluoro-methyl)trimethylsilane (535 μL, 3.62 mmol) was added at 0° C.Thereafter, tetra-n-butylammonium fluoride (TBAF, 1 M tetrahydrofuransolution) (362 μL, 0.36 mmol) was added dropwise thereto, and theobtained solution was stirred at room temperature for 6 hours. To thereaction solution, tetra-n-butylammonium fluoride (TBAF, 1 Mtetrahydrofuran solution) (3.29 mL, 3.29 mmol) was added. The obtainedmixture was stirred at room temperature for 1 hour, and then poured into1 M hydrochloric acid. The reaction solution was extracted with diethylether. The organic layer was washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, n-hexane/ethyl acetate) toobtain the title compound (410 mg, 0.92 mmol, 56%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.60 (1H, s), 1.87-2.02 (4H, m), 2.09-2.02(2H, m), 2.34-2.40 (6H, m), 3.82 (3H, s), 6.47 (1H, s), 6.86 (2H, d,J=8.8 Hz), 7.08-7.11 (4H, m), 7.20 (2H, d, J=8.8 Hz).

IR (KBr, cm⁻¹): 3402, 2954, 1517, 1463, 1305, 1250, 1249, 1179, 1121,1056, 1024, 834.

ESI-MS: m/z=447 (M+H)⁺

Example 634-Methoxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexanol

To a solution ofc-4-methoxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-ylacetate (Reference Example 79) (124 mg, 0.284 mmol) in methanol (2.8mL), potassium carbonate (197 mg, 1.42 mmol) was added, and the obtainedsolution was stirred at room temperature for 18 hours. Water was addedto the reaction solution to quench the reaction, and the resultingsolution was extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the title compound (102mg, 0.260 mmol, 91%) as a white amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.78-1.88 (2H, m), 1.90-1.99 (4H, m),2.03-2.09 (2H, m), 2.33 (3H, s), 2.49 (1H, s), 3.24-3.32 (1H, m), 3.39(3H, s), 3.81 (3H, s), 6.39 (1H, s), 6.85 (2H, d, J=8.8 Hz), 7.09 (4H,s), 7.20 (2H, d, J=8.8 Hz).

IR (KBr, cm⁻¹): 3425, 2937, 1516, 1443, 1369, 1300, 1249, 1171, 1099,1030, 968, 834, 801.

ESI-MS: m/z=393 (M+H)⁺

Example 644-Hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-cyclohexanecarboxylicacid

To a solution ofc-4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexan-r-1-carbaldehyde(Reference Example 82) (124.9 mg, 0.32 mmol) in t-butanol (2.4 ml),distilled water (0.8 ml) and 2-methyl-2-butene (101 μl, 0.96 mmol) wereadded, and the obtained solution was cooled in ice. At 0° C., sodiumdihydrogen phosphate (42.1 mg, 0.35 mmol) and sodium chlorite (72.3 mg,0.80 mmol) were added thereto, and the obtained mixture was stirred for5 minutes. The mixture was warmed to room temperature, and stirred for 1hour, and then cooled to 0° C. Thereafter, aqueous sodium thiosulfatesolution was added thereto, and the resulting mixture was stirred. Tothe mixture, 1 M hydrochloric acid and ethyl acetate were added, and theresulting solution was extracted. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the title compound (116.6mg, 0.29 mmol, 93%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.87-2.11 (9H, m), 2.33 (3H, s), 2.40-2.43(1H, m), 3.81 (3H, s), 6.38 (1H, s), 6.84 (2H, d, J=9.2 Hz), 7.09-7.09(4H, m), 7.20 (2H, d, J=9.2 Hz).

IR (KBr, cm⁻¹): 3523, 2928, 1706, 1517, 1252, 831.

ESI-MS: m/z=407 (M+H)⁺

Example 654-(Hydroxymethyl)-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-trans-1,4-cyclohexanol(65-A)

4-(Hydroxymethyl)-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-1,4-cyclohexanol

To a solution of4-(benzyloxymethyl)-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)cyclohexan-1-one(Reference Example 91) (387 mg, 0.804 mmol) in methanol (8.0 mL), sodiumborohydride (30.4 mg, 0.804 mmol) was added. The obtained solution wasstirred at room temperature for 1 hour, and then poured into 1 Mhydrochloric acid. The reaction solution was extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure to obtain theresidue.

To a solution of the obtained residue in methanol (8.0 mL), underhydrogen atmosphere, 10% palladium carbon (86.0 mg, 0.080 mmol) wasadded, and the obtained solution was stirred at room temperature for 3hours. The reaction solution was filtered through Celite, andconcentrated under reduced pressure. The residue was purified by flashchromatography (amine silica gel, n-hexane/ethyl acetate) to obtain thetitle compound 65-A (51.6 mg, 0.131 mmol, 16%) as a white solid, and thetitle compound 65-B (164 mg, 0.418 mmol, 52%) as a white amorphousproduct.

65-A: ¹H-NMR (400 MHz, CDCl₃) δ: 1.43 (1H, brs), 1.54-1.67 (2H, m),1.83-1.91 (4H, m), 2.00-2.08 (2H, m), 2.34 (3H, s), 3.24-3.33 (1H, m),3.78-3.86 (6H, m), 6.32 (1H, s), 6.84 (2H, d, J=8.8 Hz), 7.10 (4H, s),7.19 (2H, d, J=8.8 Hz).

ESI-MS: m/z=393 (M+H)⁺

65-B: ¹H-NMR (400 MHz, CDCl₃) δ: 1.39 (1H, d, J=4.8 Hz), 1.46-1.60 (4H,m), 1.85-1.95 (2H, m), 2.33-2.40 (5H, m), 2.71 (1H, t, J=6.4 Hz), 3.55(2H, d, J=6.4 Hz), 3.71-3.83 (4H, m), 6.37 (1H, s), 6.85 (2H, d, J=8.8Hz), 7.10 (4H, s), 7.20 (2H, d, J=8.8 Hz).

ESI-MS: m/z=393 (M+H)⁺

Example 664-(4,5-Bis(4-methoxyphenyl)oxazol-2-yl)-4-hydroxycyclohexanone

To a solution of8-(4,5-bis(4-methoxyphenyl)oxazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol(Reference Example 92) (781 mg, 1.78 mmol) in tetrahydrofuran (4.5 mL),6 M hydrochloric acid (9.0 mL) was added at 0° C., and the obtainedsolution was stirred at room temperature for 2 hours. The reactionsolution was cooled to 0° C., and alkalified by addition of 10% aqueoussodium hydroxide solution and saturated sodium bicarbonate solution. Theresulting solution was extracted with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by recrystallization (ethylacetate/n-hexane) to obtain the title compound (445 mg, 1.13 mmol, 63%)as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.32-2.54 (6H, m), 2.81-2.92 (2H, m), 3.17(1H, m), 3.84 (6H, s), 6.90 (2H, d, J=8.8 Hz), 6.91 (2H, d, J=8.8 Hz),7.49 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz).

ESI-MS: m/z=394 (M+H)⁺

Example 674-(4,5-Bis(4-methoxyphenyl)oxazol-2-yl)cyclohexan-trans-1,4-diol (67-A)

4-(4,5-Bis(4-methoxyphenyl)oxazol-2-yl)cyclohexan-cis-1,4-diol (67-B)

To a solution of4-hydroxy-4-(4,5-bis(4-methoxyphenyl)oxazol-2-yl)cyclohexan-1-one(Example 66) (395 mg, 1.00 mmol) in methanol (20 mL), sodium borohydride(47 mg, 1.24 mmol) was added, and the obtained solution was stirred atroom temperature for 16 hours. The reaction solution was concentratedunder reduced pressure, and distilled water was added to the residue.The resulting solution was extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the title compound 67-A(73 mg, 0.18 mmol, 18%) as a white solid, and the title compound 67-B(207 mg, 0.523 mmol, 52%) as a white solid.

67-A: ¹H-NMR (400 MHz, CDCl₃) δ: 1.63-1.75 (2H, m), 1.78-1.88 (2H, m),2.01-2.12 (2H, m), 2.44-2.53 (2H, m), 2.67 (1H, s), 4.00-4.07 (1H, m),6.89 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz),7.57 (2H, d, J=8.8 Hz).

IR (KBr, cm⁻¹): 3356, 1613, 1600, 1520, 1503, 1254, 1182, 1033, 999,966, 834.

ESI-MS: m/z=396 (M+H)⁺

67-B: ¹H-NMR (400 MHz, CDCl₃) δ: 1.49 (1H, brs), 1.78-2.13 (8H, m), 2.76(1H, s), 3.72-3.78 (1H, m), 3.83 (6H, s), 6.89 (2H, d, J=8.8 Hz), 6.90(2H, d, J=8.8 Hz), 7.49 (2H, d, J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz).

IR (KBr, cm⁻¹): 3364, 1615, 1599, 1520, 1500, 1302, 1252, 1176, 1069,1053, 1028, 965, 833.

ESI-MS: m/z=396 (M+H)⁺

Example 684-Hydroxy-4-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)cyclohexan-1-one

To a solution of8-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol(Reference Example 96) (469 mg, 1.07 mmol) in tetrahydrofuran (5.4 mL),6 M hydrochloric acid (5.4 mL) was added at 0° C., and the obtainedsolution was stirred at room temperature for 14 hours. The reactionsolution was basified by pouring it into saturated aqueous sodiumhydrogen carbonate solution, and the resulting mixture was extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel, n-hexane/ethylacetate) to obtain the title compound (352 mg, 0.895 mmol, 83%) as awhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.33-2.51 (6H, m), 2.37 (3H, s), 2.86-2.95(2H, m), 3.50 (1H, s), 3.81 (3H, s), 6.81-6.84 (2H, m), 7.14 (2H, d,J=8.0 Hz), 7.24 (2H, d, J=8.0 Hz), 7.44-7.48 (2H, m).

ESI-MS: m/z=394 (M+H)⁺

Example 691-(4-(4-Methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)cyclohexan-trans-1,4-diol(69-A)

1-(4-(4-Methoxyphenyl)-5-p-tolylthiazol-2-yl)cyclohexan-cis-1,4-diol(69-B)

To a solution of4-hydroxy-4-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)cyclohexan-1-one(Example 68) (186 mg, 0.471 mmol) in methanol (4.7 mL), sodiumborohydride (36 mg, 0.943 mmol) was added, and the obtained solution wasstirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure, and then dissolved into ethylacetate, and washed with distilled water and brine. The organic layerwas dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by flash chromatography (silica gel,n-hexane/ethyl acetate) to obtain the title compound 69-A (42 mg, 0.106mmol, 23%) as a white solid, and the title compound 69-B (136 mg, 0.344mmol, 73%) as a white solid.

69-A: ¹H-NMR (400 MHz, CDCl₃) δ: 1.53-1.57 (1H, m), 1.76-1.87 (4H, m),2.05-2.12 (2H, m), 2.35-2.42 (2H, m), 2.36 (3H, s), 3.15 (1H, br), 3.80(3H, s), 4.10-4.14 (1H, m), 6.80-6.84 (2H, m), 7.13 (2H, d, J=8.0 Hz),7.24 (2H, d, J=8.0 Hz), 7.45-7.49 (2H, m).

IR (KBr, cm⁻¹): 3409, 2923, 1613, 1515, 1252, 1179, 1004, 815.

ESI-MS: m/z=396 (M+H)⁺

69-B: ¹H-NMR (400 MHz, CDCl₃) δ: 1.48 (1H, d, J=4.8 Hz), 1.82-1.89 (2H,m), 1.95-2.01 (2H, m), 2.05-2.09 (4H, m), 2.36 (3H, s), 3.01 (1H, s),3.76-3.82 (1H, m), 3.80 (3H, s), 6.80-6.83 (2H, m), 7.13 (2H, d, J=8.0Hz), 7.22 (2H, d, J=8.0 Hz), 7.43-7.47 (2H, m).

IR (KBr, cm⁻¹): 3418, 2938, 1611, 1515, 1249, 1177, 1058, 816.

ESI-MS: m/z=396 (M+H)⁺

Example 701-(4-(4-Methoxyphenyl)-5-p-tolylthiazol-2-yl)-4-(trifluoromethyl)cyclohexan-trans-1,4-diol(70-A)1-(4-(4-Methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-4-(trifluoromethyl)cyclohexan-cis-1,4-diol(70-B)

To a solution of4-hydroxy-4-(4-(4-methoxyphenyl)-5-p-tolylthiazol-2-yl)cyclohexan-1-one(Example 68) (199 mg, 0.506 mmol) and Ruppert's reagent (0.187 mL, 1.26mmol) in tetrahydrofuran (2.5 mL), 1.0 M tetrabutylammoniumfluoride/tetrahydrofuran solution (0.051 mL, 0.051 mmol) was added atroom temperature, and the obtained solution was stirred for 10 minutes.The reaction solution was concentrated under reduced pressure, anddissolved into tetrahydrofuran (3.0 mL). Distilled water (0.2 mL) and1.0 M tetrabutylammonium fluoride/tetrahydrofuran solution (1.02 mL,1.02 mmol) were added thereto, and the resulting mixture was stirred atroom temperature for 30 minutes. Distilled water was added to thereaction solution, and the resulting solution was extracted with ethylacetate, followed by washing with brine. The organic layer was driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by flash chromatography (silica gel,n-hexane/ethyl acetate) to obtain the title compound 70-A (70 mg, 0.151mmol, 30%) as a white solid, and the title compound 70-A (132 mg, 0.285mmol, 56%) as a white solid.

70-A: ¹H-NMR (400 MHz, CDCl₃) δ: 1.79-1.84 (2H, m), 1.90 (1H, s),1.96-2.01 (2H, m), 2.21-2.33 (4H, m), 2.37 (3H, s), 3.28 (1H, s), 3.80(3H, s), 6.80-6.84 (2H, m), 7.13 (2H, d, J=8.0 Hz), 7.23 (2H, d, J=8.0Hz), 7.44-7.48 (2H, m).

IR (KBr, cm⁻¹): 3460, 2940, 1610, 1515, 1494, 1442, 1310, 1245, 1175,1035, 1005, 837, 813

ESI-MS: m/z=464 (M+H)⁺

70-B: ¹H-NMR (400 MHz, CDCl₃) δ: 1.90-1.96 (2H, m), 1.97 (1H, br),2.16-2.23 (2H, m), 2.28-2.36 (4H, m), 2.37 (3H, s), 2.81 (1H, br), 3.80(3H, s), 6.80-6.83 (2H, m), 7.14 (2H, d, J=8.0 Hz), 7.26 (2H, d, J=8.0Hz), 7.44-7.48 (2H, m).

IR (KBr, cm⁻¹): 3419, 2940, 1611, 1515, 1443, 1290, 1250, 1175, 1120,1066, 993, 837, 814

ESI-MS: m/z=464 (M+H)⁺

Example 71 Ethyl4-hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-cyclohexanecarboxylate

To a solution of4-hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-cyclohexanecarboxylicacid (Example 64) (41.6 mg, 0.10 mmol) in DMF (1.0 ml), potassiumcarbonate (41.4 mg, 0.3 mmol) and ethyl iodide (24.8 μl, 0.3 mmol) wereadded, and the obtained solution was stirred for 2 hours. Brine wasadded to the reaction solution, and the resulting solution was extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by flash column chromatography (silica gel,n-hexane/ethyl acetate) to obtain the title compound (44.1 mg, 0.10mmol, 97%) as a white amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.27 (3H, t, J=6.8 Hz), 1.85-2.09 (8H, m),2.33 (3H, s), 2.34-2.41 (1H, m), 2.59 (1H, s), 3.80 (3H, s), 4.15 (2H,q, J=6.8 Hz), 6.38 (1H, s), 6.84 (2H, d, J=8.8 Hz), 7.09-7.09 (4H, m),7.20 (2H, d, J=8.8 Hz).

ESI-MS: m/z=435 (M+H)⁺

The compounds of the following Comparative Examples 1 to 25 wereprepared by the same procedure as in the above Examples 2 to 6.

TABLE 9 Comparative Example Structural Formula Compound Data 1

¹H-NMR (400 MHz, CDCl₃) δ: 1.67-1.73 (3H, m), 1.80-1.86 (2H, m), 2.00(3H, s), 2.05-2.12 (2H, m), 2.33-2.40 (2H, m), 2.59 (1H, s), 3.76 (3H,s), 4.03-4.06 (1H, m), 6.35 (1H, s), 6.72 (2H, d, J = 8.8 Hz), 7.11-7.21(6H, m). ESI-MS: m/z = 379 (M + H)⁺ 2

¹H-NMR (400 MHz, CDCl₃) δ: 1.85-1.99 (10H, m), 2.06-2.09 (2H, m), 2.66(1H, s), 3.75-3.75 (4H, m), 6.28 (1H, s), 6.75 (2H, d, J = 9.2 Hz), 7.12(2H, d, J = 9.2 Hz), 7.14-7.20 (3H, m), 7.24-7.28 (1H, m). IR (KBr,cm⁻¹): 3326, 2939, 1516, 1249, 1069, 834. ESI-MS: m/z = 361 (M − OH)⁺,379 (M + H)⁺ 3

¹H-NMR (400 MHz, CDCl₃) δ: 1.63-1.83 (5H, m), 2.03-2.12 (2H, m),2.32-2.39 (2H, m), 2.58 (1H, s), 3.07 (3H, s), 3.83 (3H, s), 4.04-4.06(1H, m), 6.57 (1H, s), 6.88 (2H, d, J = 8.8 Hz), 7.19 (2H, d, J = 8.8Hz), 7.40 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz). ESI-MS: m/z =443 (M + H)⁺ 4

¹H-NMR (400 MHz, CDCl₃) δ: 1.80-2.00 (9H, m), 3.06 (3H, s), 3.71-3.80(1H, m), 3.82 (3H, s), 6.53 (1H, s), 6.88 (2H, d, J = 8.8 Hz), 7.17 (2H,d, J = 8.8 Hz), 7.39 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz).ESI-MS: m/z = 443 (M + H)⁺ 5

¹H-NMR (400 MHz, CDCl₃) δ: 1.34 (1H, brs), 1.64-1.73 (2H, m), 1.76-1.84(2H, m), 2.03-2.12 (2H, m), 2.30-2.40 (2H, m), 2.45 (1H, brs), 4.03-4.10(1H, m), 6.48 (1H, s), 7.02-7.08 (2H, m), 7.12-7.17 (2H, m), 7.23-7.32(4H, m). ESI-MS: m/z = 387 (M + H)⁺ 6

¹H-NMR (400 MHz, CDCl₃) δ: 1.45 (1H, d, J = 5.2 Hz), 1.80-2.09 (8H, m),2.45 (1H, s), 3.70-3.80 (1H, m), 6.43 (1H, s), 7.01-7.08 (2H, m),7.11-7.16 (2H, m), 7.22-7.31 (4H, m). ESI-MS: m/z = 387 (M + H)⁺ 7

¹H-NMR (400 MHz, CDCl₃) δ: 1.34 (1H, brs), 1.63-1.71 (2H, m), 1.77-1.84(2H, m), 2.03-2.11 (2H, m), 2.32-2.40 (3H, m), 4.01-4.08 (1H, m), 6.53(1H, s), 7.09-7.12 (2H, m), 7.24-7.27 (2H, m), 7.32 (1H, dd, J = 8.4,2.0 Hz), 7.36 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 2.0 Hz). ESI-MS: m/z= 437 (M + H)⁺ 8

¹H-NMR (400 MHz, CDCl₃) δ: 1.44 (1H, d, J = 4.8 Hz), 1.79-2.09 (8H, m),2.37 (1H, s), 3.70-3.80 (1H, m), 6.49 (1H, s), 7.08-7.11 (2H, m),7.24-7.27 (2H, m), 7.32 (1H, dd, J = 8.4, 2.0 Hz), 7.35 (1H, d, J = 8.4Hz), 7.45 (1H, d, J = 2.0 Hz). ESI-MS: m/z = 437 (M + H)⁺ 9

¹H-NMR (400 MHz, CDCl₃) δ: 1.34 (1H, d, J = 3.6 Hz), 1.64-1.73 (2H, m),1.77-1.84 (2H, m), 2.04-2.12 (2H, m), 2.30 (3H, s), 2.31-2.40 (2H, m),2.56 (1H, s), 3.81 (3H, s), 4.02-4.08 (1H, m), 6.45 (1H, s), 6.85 (2H,d, J = 9.2 Hz), 6.93-6.97 (1H, m), 7.09-7.18 (3H, m), 7.22 (2H, d, J =9.2 Hz). ESI-MS: m/z = 379 (M + H)⁺ 10

¹H-NMR (400 MHz, CDCl₃) δ: 1.43 (1H, d, J = 4.8 Hz), 1.83-2.00 (6H, m),2.03-2.09 (2H, m), 2.29 (3H, s), 2.56 (1H, s), 3.70-3.78 (1H, m), 3.81(3H, s), 6.39 (1H, s), 6.84 (2H, d, J = 8.8 Hz), 6.92-6.96 (1H, m),7.08-7.18 (3H, m), 7.20 (2H, d, J = 8.8 Hz). ESI-MS: m/z = 379 (M + H)⁺11

¹H-NMR (400 MHz, CDCl₃) δ: 1.36 (1H, brs), 1.64-1.72 (2H, m), 1.77-1.83(2H, m), 2.04-2.12 (2H, m), 2.32-2.39 (2H, m), 2.35 (3H, s), 2.51 (1H,s), 4.03-4.08 (1H, m), 6.44 (1H, s), 6.99-7.05 (2H, m), 7.09 (2H, d, J =8.4 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.24-7.30 (2H, m). IR (KBr, cm⁻¹):3342, 2921, 1516, 1439, 1368, 1227, 1196, 1156, 1005, 840, 810. ESI-MS:m/z = 367 (M + H)⁺ 12

¹H-NMR (400 MHz, CDCl₃) δ: 1.50 (1H, brs), 1.80-1.99 (6H, m), 2.02-2.08(2H, m), 2.35 (3H, s), 2.54 (1H, s), 3.71-3.78 (1H, m), 6.39 (1H, s),6.99-7.05 (2H, m), 7.08 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.4 Hz),7.23-7.28 (2H, m). IR (KBr, cm⁻¹): 3374, 2938, 2876, 1515, 1436, 1416,1362, 1238, 1192, 1167, 1111, 1092, 1064, 1018, 973, 886, 843, 799.ESI-MS: m/z = 349 (M − OH)⁺ 13

¹H-NMR (400 MHz, CDCl₃) δ: 1.54 (1H, brs), 1.64-1.72 (2H, m), 1.77-1.84(2H, m), 2.04-2.12 (2H, m), 2.32-2.39 (2H, m), 2.52 (1H, s), 3.82 (3H,s), 4.03-4.08 (1H, m), 6.44 (1H, s), 6.84-6.88 (2H, m), 6.96-7.02 (2H,m), 7.16-7.21 (4H, m). IR (KBr, cm⁻¹): 3355, 2931, 1516, 1249, 1003,830. ESI-MS: m/z = 383 (M + H)⁺ 14

¹H-NMR (400 MHz, CDCl₃) δ: 1.45 (1H, brs), 1.80-2.00 (6H, m), 2.02-2.09(2H, m), 2.53 (1H, s), 3.70-3.78 (1H, m), 3.81 (3H, s), 6.39 (1H, s),6.83-6.88 (2H, m), 6.96-7.01 (2H, m), 7.16-7.20 (4H, m). IR (KBr, cm⁻¹):3412, 2937, 1609, 1517, 1444, 1300, 1251, 1159, 1066, 971, 839. ESI-MS:m/z = 365 (M − OH)⁺ 15

¹H-NMR (400 MHz, CDCl₃) δ: 1.42 (I H, brs), 1.63-1.72 (2H, m), 1.76-1.83(2H, m), 2.03-2.11 (2H, m), 2.31-2.38 (2H, m), 2.50 (1H, s), 4.04-4.09(1H, m), 6.46 (1H, s), 7.00-7.05 (2H, m), 7.17-7.22 (4H, m), 7.29-7.32(2H, m). IR (KBr, cm⁻¹): 3366, 2936, 1499, 1362, 1231, 1002, 840,ESI-MS: m/z = 387 (M + H)⁺ 16

¹H-NMR (400 MHz, CDCl₃) δ: 1.46 (1H, brs), 1.80-1.99 (6H, m), 2.02-2.08(2H, m), 2.47 (1H, s), 3.70-3.79 (1H, m), 6.41 (1H, s), 7.00-7.05 (2H,m), 7.17-7.22 (4H, m), 7.28-7.32 (2H, m). IR (KBr, cm⁻¹): 3459, 2937,1602, 1500, 1374, 1231, 1071, 963. ESI-MS: m/z = 369 (M − OH)⁺ 17

¹H-NMR (400 MHz, CDCl₃) δ: 1.45 (1H, brs), 1.64-1.72 (2H, m), 1.77-1.83(2H, m), 2.03-2.12 (2H, m), 2.31-2.39 (2H, m), 2.51 (1H, br), 4.03-4.08(1H, m), 6.46 (1H, s), 6.98-7.06 (4H, m), 7.11-7.20 (2H, m), 7.23-7.26(2H, m). IR (KBr, cm⁻¹): 3399, 2933, 1609, 1515, 1444, 1368, 1228, 1159,1073, 999, 840, 815. ESI-MS: m/z = 371 (M + H)⁺ 18

¹H-NMR (400 MHz, CDCl₃) δ: 1.47 (1H, brs), 1.80-2.00 (6H, m), 2.02-2.07(2H, m), 2.48 (1H, s), 3.71-3.79 (1H, m), 6.41 (1H, s), 6.98-7.06 (4H,m), 7.15-7.20 (2H, m), 7.22-7.26 (2H, m). IR (KBr, cm⁻¹): 3369, 2941,1609, 1515, 1236, 1159, 1066, 973, 841. ESI-MS: m/z = 353 (M − OH)⁺ 19

¹H-NMR (400 MHz, CDCl₃) δ: 1.40 (1H, brs), 1.65-1.72 (2H, m), 1.78-1.84(2H, m), 104-2.12 (2H, m), 2.32-2.40 (2H, m), 2.55 (1H, s), 4.04-4.08(1H, m), 6.46 (1H, s), 6.97-7.02 (2H, m), 7.17-7.22 (2H, m), 7.27-7.36(5H, m). IR (KBr, cm⁻¹): 3361, 2932, 1604, 1502, 1438, 1363, 1231, 1000,812, 766. ESI-MS: m/z = 353 (M + H)⁺ 20

¹H-NMR (400 MHz, CDCl₃) δ: 1.45-1.46 (1H, m), 1.81-2.01 (6H, m),2.02-2.09 (2H, m), 2.54 (1H, s), 3.71-3.79 (1H, m), 6.41 (1H, s),6.97-7.02 (2H, m), 7.16-7.21 (2H, m), 7.25-7.28 (2H, m), 7.30-7.36 (3H,m). IR (KBr, cm⁻¹): 3349, 2941, 1601, 1502, 1436, 1359, 1232, 1066, 834.ESI-MS: m/z = 335 (M − OH)⁺ 21

¹H-NMR (400 MHz, CDCl₃) δ: 1.38 (1H, brs), 1.64-1.72 (2H, m), 1.77-1.84(2H, m), 2.04-2.12 (2H, m), 2.32-2.39 (2H, m), 2.36 (3H, s), 2.56 (1H,s), 4.03-4.08 (1H, m), 6.44 (1H, s), 6.96-7.02 (2H, m), 7.12-7.21 (6H,m). IR (KBr, cm⁻¹): 3363, 2926, 1613, 1509, 1440, 1364, 1231, 1001, 818.ESI-MS: m/z = 367 (M + H)⁺ 22

¹H-NMR (400 MHz, CDCl₃) δ: 1.43(1H, brs), 1.65-1.73 (2H, m), 1.76-1.83(2H, m), 2.04-2.12 (2H, m), 2.32-2.39 (2H, m), 2.38 (3H, s), 2.48 (1H,br), 3.06 (3H, s), 4.05-4.09 (1H, m), 6.49 (1H, s), 7.12 (2H, d, J = 8.0Hz), 7.16 (2H, d, J = 8.0 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.88 (2H, d, J= 8.4 Hz). IR (KBr, cm⁻¹): 3422, 2930, 1594, 1504, 1364, 1306, 1150,958, 781. ESI-MS: m/z = 427 (M + H)⁺ 23

¹H-NMR (400 MHz, CDCl₃) δ: 1.44-1.46 (1H, m), 1.84-2.00 (6H, m),2.03-2.08 (2H, m), 2.38 (3H, s), 2.46 (1H, s), 3.05 (3H, s), 3.74-3.78(1H, m), 6.44 (1H, s), 7.11 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 8.0Hz), 7.49 (2H, d, J = 8.4 Hz), 7.88 (2H, d, J = 8.4 Hz). IR (KBr, cm⁻¹):3402, 2932, 1594, 1505, 1364, 1305, 1153, 961, 780. ESI-MS: m/z = 409 (M− OH)⁺ 24

¹H-NMR (400 MHz, CDCl₃) δ: 1.37 (1H, s), 1.67-1.72 (2H, m), 1.79-1.85(2H, m), 2.05-2.09 (2H, m), 2.33-2.37 (2H, m), 2.54 (1H, s), 3.67 (3H,s), 3.79 (3H, s), 4.06-4.10 (1H, m), 6.50 (1H, s), 6.82 (2H, d, J = 8.8Hz), 6.87 (1H, dd, J = 5.2, 7.2 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.46 (1H,d, J = 2.0, 7.2 Hz), 8.15 (1H, d, J = 2.0, 5.2 Hz). ESI-MS: m/z = 396(M + H)⁺ 25

¹H-NMR (400 MHz, CDCl₃) δ: 1.44-1.46 (1H, m), 1.87-1.97 (6H, m),2.05-2.06 (2H, m), 2.52 (1H, s), 3.67 (3H, s), 3.74-3.79 (4H, s), 6.45(1H, s), 6.82 (2H, d, J = 8.8 Hz), 6.87 (1H, dd, J = 5.2, 7.2 Hz), 7.17(2H, d, J = 8.8 Hz), 7.45 (1H, d, J = 2.0, 7.2 Hz), 8.14 (1H, d, J =2.0, 5.2 Hz). ESI-MS: m/z = 396 (M + H)⁺

Comparative Example 26c-4-Hydroxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-ylacetate

To a solution of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-cis-1,4-diyldiacetate (Reference Example 78) (297 mg, 0.642 mmol) in methanol (4.3mL), potassium carbonate (89.0 mg, 0.642 mmol) was added, and theobtained solution was stirred at room temperature for 4 hours. Water wasadded to the reaction solution to quench the reaction, and the resultingsolution was extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the title compound (213mg, 0.507 mmol, 79%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.49 (1H, d, J=4.4 Hz), 1.65-1.74 (2H, m),1.90-1.98 (4H, m), 2.10 (3H, s), 2.32 (3H, s), 2.71-2.78 (2H, m),3.74-3.81 (4H, m), 6.37 (1H, s), 6.83 (2H, d, J=9.2 Hz), 7.08 (4H, s),7.20 (2H, d, J=9.2 Hz).

ESI-MS: m/z=421 (M+H)⁺

Comparative Example 274-Methoxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)cyclohexanol

To a solution ofc-4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-ylacetate (Example 57) (200 mg, 0.476 mmol) in N,N-dimethylformamide (2.4mL), 55% sodium hydride (31.1 mg, 0.713 mmol) and methyl iodide (39.0μL, 0.618 mmol) were added with stirring under ice-cooling. The obtainedsolution was stirred at room temperature for 60 hours. Water was addedto the reaction solution with stirring under ice-cooling, and theresulting solution was stirred for 15 minutes, followed by extractionwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel, n-hexane/ethylacetate) and further purified by reprecipitation and washing(n-hexane/diethyl ether) to obtain the title compound (60.5 mg, 0.139mmol, 29%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.42 (1H, brs), 1.70-1.78 (2H, m), 1.84-1.95(4H, m), 2.25-2.34 (5H, m), 3.18 (3H, s), 3.68-3.77 (1H, m), 3.81 (3H,s), 6.43 (1H, s), 6.84 (2H, d, J=8.8 Hz), 7.10 (4H, s), 7.20 (2H, d,J=8.8 Hz).

IR (KBr, cm⁻¹): 3407, 2937, 1516, 1457, 1368, 1298, 1249, 1185, 1071,1035, 969, 833.

ESI-MS: m/z=393 (M+H)⁺

Comparative Example 281-(4-Fluoro-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-cis-1,4-diol

To a solution of4-(4-fluoro-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-c-4-hydroxy-cyclohexan-r-1-ylacetate (Reference Example 80) (90 mg, 0.205 mmol) in methanol (2.0 mL),potassium carbonate (142 mg, 1.03 mmol) was added, and the obtainedsolution was stirred at room temperature for 2 hours. Water was added tothe reaction solution to quench the reaction, and the resulting solutionwas extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel, n-hexane/ethyl acetate) to obtain the title compound (62mg, 0.156 mmol, 76%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.45 (1H, s), 1.83-1.95 (4H, m), 2.06-2.08(4H, m), 2.36 (3H, s), 2.70 (1H, s), 3.77-3.81 (4H, m), 6.83-6.86 (2H,m), 7.12-7.19 (6H, m).

ESI-MS: m/z=379 (M−OH)⁺

Comparative Example 294-(4-Fluoro-1-(4-methoxyphenyl)-5-(4-tolyl)-1H-pyrazol-3-yl)-1-(N-hydroxy-N-methylcarbamoyl)-4-piperidinol

To a solution of4-(4-fluoro-1-(4-methoxyphenyl)-5-(4-tolyl)-1H-pyrazol-3-yl)-4-piperidinol(3.61 g, 9.46 mmol) in tetrahydrofuran (946 mL), triphosgene (1.12 g,3.78 mmol) and triethylamine (1.65 mL, 11.8 mmol) were added at 0° C.,and the obtained solution was stirred at the same temperature for 40minutes. To the reaction solution, N-methylhydroxylamine hydrochloride(988 mg, 11.8 mmol) and triethylamine (3.43 mL, 24.6 mmol) were added,and the obtained mixture was stirred at 80° C. for 3 hours. The reactionsolution was cooled to room temperature, and distilled water was addedto the reaction solution. The resulting solution was extracted withethyl acetate. The organic layer was washed with 1 M hydrochloric acid,saturated sodium bicarbonate solution and brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by recrystallization (n-hexane/ethyl acetate, 80° C.) to obtainthe title compound (2.96 g, 6.51 mmol, 68%) as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.94-1.98 (2H, m), 2.23-2.31 (2H, m), 2.35(3H, s), 2.86 (1H, s), 3.00 (3H, s), 3.50-3.56 (2H, m), 3.81 (3H, s),3.92-3.95 (2H, m), 6.84-6.87 (3H, m), 7.10-7.19 (6H, m).

IR (KBr, cm⁻¹): 3382, 1630, 1513, 1440, 1251, 1164, 1108, 1031, 836.

ESI-MS: m/z=438 (M−OH)⁺

Comparative Example 304-(3-Cyclohexyl-5-phenyl-1H-pyrazol-1-yl)-2-(hydroxymethyl)benzenesulfonamide

To a suspension of 4-hydrazinyl-2-(hydroxymethyl)benzenesulfonamide (224mg, 0.884 mmol) in ethanol (4.0 mL), triethylamine (246 μL, 1.77 mmol)and 1-cyclohexyl-3-phenylpropan-1,3-dione (185 mg, 0.803 mmol) wereadded, and the obtained solution was stirred at 100° C. for 72 hours.Water was added to the reaction solution, and the resulting solution wasextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by flash chromatography (silica gel,n-hexane/chloroform/acetone) to obtain the title compound (51.5 mg,0.125 mmol, 16%) as a white amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.18-1.89 (8H, m), 1.98-2.09 (2H, m),2.69-2.79 (1H, m), 3.28 (1H, br), 4.94 (2H, d, J=5.2 Hz), 5.56-5.63 (2H,m), 6.35 (1H, s), 7.05-7.38 (6H, m), 7.48-7.54 (1H, m), 7.83 (1H, d,J=8.8 Hz).

ESI-MS: m/z=412 (M+H)⁺

Example 72 Effect on Nociceptive Pain

Using a mouse acetic acid writhing model with which nociceptive pain canbe evaluated, the analgesic effect of Compound (I) was studied.

1. Experimental Method

Male ddY mice of 5 to 6 weeks old were fasted for not less than 16hours, during which water was given ad libitum. Thereafter, the testcompound solution or its vehicle was orally administered (10 mL/kg). Asthe vehicle of the test compound solution, dimethyl sulfoxide(hereinafter referred to as DMSO):Tween 80:distilled water (1:1:8) or27% hydroxypropyl-β-cyclodextrin (hereinafter referred to as HP-β-CD)was used. Forty five minutes after the administration of the vehicle ortest compound, 0.6% acetic acid solution (10 mL/kg) wasintraperitoneally administered to induce writhing responses (behaviorssuch as extending the body and bending the body backward). The number ofwrithing responses occurred from 10 minutes after the administration ofthe acetic acid solution was counted for 10 minutes, and the number ofwrithing responses was used as an index of pain.

The mean number of writhing responses obtained in the vehicle group wasdefined as 100%, and the dose of the test compound with which 50% of theresponse was suppressed was represented as the ED₅₀ value.

2. Results

Results are shown in Table 10.

TABLE 10 ED₅₀ Compound (mg/kg) Vehicle Example 1 3.78 A Example 2-A 1.80A Example 2-B 1.40 A Example 3 6.07 B Example 6-A 7.97 B Example 28 5.27B Example 29 3.77 A Example 30 3.73 B Example 31 0.41 B Example 33 2.69B Example 35 4.69 B Example 37 1.95 A Example 57 1.77 B Example 59 9.92B Example 60 1.37 B Example 62 0.54 B Example 63 5.36 B Example 64 1.19B Example 65-A 1.44 B Example 67-B 7.32 B Example 69-A 3.02 A Example70-B 9.65 B Example 71 1.58 A Comparative >10 Comparative Examples 8,24, 26 A Example 1 Comparative Examples 1 to 7, 9 to 23, 25, B to 28 27Comparative >10 B Example 30 Vehicle A = DMSO:Tween 80:distilled water(1:1:8), vehicle B = 27% HP-β-CD

All the compounds of Examples 1,2-A, 2-B, 3,6-A, 28-31, 33, 35, 37, 57,59, 60, 62˜64, 65-A, 67-B, 69-A, 70-B and 71 described in Table 10showed ED₅₀ values of 0.41 to 9.92 mg/kg. In terms of ComparativeExamples 1 to 28, the ED₅₀ values were >10 mg/kg. These results indicatethat Compound (I) has an excellent analgesic effect. Further, thecompound of Comparative Example 30 did not cause significant reductionin the number of writhing responses even by administration of 10 mg/kgof the compound (t-test).

Example 73 Effect in Mouse Sciatic Nerve-Ligation Model

Using a mouse sciatic nerve-ligation model (Seltzer model) with whichneuropathic pain can be evaluated, the analgesic effect of Compound (I)was studied.

The neuropathic pain model was prepared according to the method bySeltzer et al. Male ICR mice of 5 weeks old were anesthetized withsodium pentobarbital (70 mg/kg, i.p.), and the sciatic nerve at thefemoral region of the right hind limb was exposed, followed by triplyand tightly ligating the sciatic nerve under microscope such that onlyhalf thickness thereof was pressed with silk suture of 8-0 (NATSUMESEISAKUSHO), to provide Ligation group. A group wherein the sciaticnerve was exposed but not ligated was provided as a control group(Sham). In terms of evaluation of neuropathic pain (hereinafter referredto as von Frey test), mice were kept in acrylic cages (NATSUMESEISAKUSHO) placed on nets for at least 1 hour for habituation, and afilament (North Coast Medical Inc. CA, USA) which exerts a pressure of0.16 g was used to mechanically stimulate the both plantar hind paws bypressing them with the filament 3 times for 3 seconds/time at intervalsof 3 seconds. The escape behavior occurred upon application of themechanical stimulation was scored (0: no response, 1: showed slow andslight escape behavior in response to the stimulation, 2: showed quickescape behavior without flinching (behavior of shaking legs quickly andcontinuously) or licking (leg-licking behavior), 3: showed quick escapebehavior with flinching or licking), and the total of the scoresobtained in the triplicate pressing trials was used as an index of pain.The von Frey test was carried out 7 days after the sciatic nerveligation operation to obtain the pre value before oral administration ofthe test compound, and also carried out 1 hour, 2 hours and 3 hoursafter the oral administration to obtain values to be used as indices ofthe analgesic effect. To provide a positive control, gabapentin (30mg/kg, oral administration) was used.

The results are shown in FIGS. 1 to 4 and Table 11. In FIGS. 1 to 4, theordinate indicates the total score of the von Frey test, and a highervalue indicates a stronger pain. The abscissa indicates the time (hr)after the administration of the test compound. As the vehicle of thetest compound solution, 27% HP-β-CD was used in the experiments of FIG.1, FIG. 3 and FIG. 4, and DMSO:Tween 80:distilled water (1:1:8) was usedin the experiment of FIG. 2. The pharmacological effect was evaluated bystatistical analysis by multiple unpaired t-test corrected withDunnett's method using the vehicle group (Ligation+Vehicle) at eachmeasurement time as a control. The symbols “*” in the Figures indicatestatistical significance (**: p<0.01, ***: p<0.001).

Based on the results of the von Frey test with the compounds of Example2-A (FIG. 1), Example 2-B (FIG. 2), Example 62 (FIG. 3) and ComparativeExample 29 (FIG. 4), gabapentin and the compound of Comparative Example29, which were positive controls, showed the strongest analgesic effect1 hour after the oral administration, and the analgesic effectdrastically decreased 3 hours after the oral administration. On theother hand, in the cases of oral administration of the compound ofExample 2-A in an amount of 0.3 mg/kg, and oral administration of thecompounds of Example 2-B and Example 62 in amounts of 0.3 and 1.0 mg/kg,respectively, a strong analgesic effect was maintained even 3 hoursafter the oral administration. From these results, it was revealed thatCompound (I) having a cyclohexane skeleton is continuously effective onneuropathic pain.

As shown in Table 11, based on the results of the von Frey test carriedout 1 hour after oral administration of the compounds of Example 4-B,Example 30, Example 31, Example 59, Example 64 and Example 67-B, all ofthese compounds significantly improved the von Frey total score comparedto the vehicle group. Thus, it was revealed that these compounds areeffective on neuropathic pain.

TABLE 11 von Frey Total Score Observed 1 Hour after Oral AdministrationScore Dose (mean±standard error) improvement (mg/kg) Control VehicleCompound- rate Compound (n = 5 to 6) group group administered group %Vehicle Example 4-B 10 0.8 ± 0.2 5.4 ± 0.4 2.2 ± 0.5** 70 A Example 3010 0.4 ± 0.2 5.0 ± 0.3 1.2 ± 0.6*** 83 A Example 31 3 0.4 ± 0.2 4.8 ±0.4 0.7 ± 0.5*** 93 B Example 59 10 0.2 ± 0.2 4.6 ± 0.5 1.7 ± 0.6** 66 AExample 64 1 0.4 ± 0.2 4.8 ± 0.4 2.3 ± 0.5* 57 C Example 67-B 10 0.8 ±0.2 5.4 ± 0.4 0.8 ± 0.7*** 100 A Vehicle A = DMSO:Tween 80:distilledwater (1:1:8), vehicle B = 27% HP-β-CD, vehicle C = 0.5% methylcellulose

In the cases where vehicle A or B was used, the compound wasadministered as a test compound solution, and in the cases where VehicleC was used, the compound was administered as a test compound suspension.

The score improvement rate was calculated as follows:

score improvement rate=100−(score of compound−administered group−scoreof control group)/(score of vehicle group−score of control group)×100.

The symbols “*” in the table indicate statistical significance (*:p<0.05, **: p<0.01, ***: p<0.001) based on comparison with the vehiclegroup (multiple unpaired t-test corrected with Dunnett's method).

Example 74 Effect on Mouse Model Having Pain Due to Diabetic Neuralgia

Using a mouse model having pain due to streptozotocin (hereinafterreferred to as STZ)-induced diabetic neuralgia, with which diabeticneuropathic pain can be evaluated, the analgesic effect of Compound (I)was studied.

STZ (250 mg/kg) or physiological saline was intraperitoneallyadministered to male ICR mice of 5 weeks old, to prepare mice havingdiabetes and a control group thereof. The mice having diabetes hereinmeans mice whose blood glucose level at full feeding is not less than350 mg/dL when a small amount of blood was collected from the tail vein6 days after administration of STZ and the blood glucose level wasmeasured using a blood glucose meter Precision Xceed and an electrodefor measurement of blood glucose Smartblue (Abbott).

Seven days after the administration of STZ, the von Frey test wascarried out for the mice having diabetes as in the above-described caseof evaluation of neuropathic pain, and individuals showing a total scoreof 5 or higher were selected as individuals having the diseased state ofpain due to diabetic neuralgia. The selected individuals were dividedinto groups such that the total score becomes even among the groups,followed by oral administration of test compounds. One hour after theoral administration, the von Frey test was further carried out, and theobtained value was used as an index of the analgesic effect. As apositive control, pregabalin (10 mg/kg, oral administration) was used.

The results are shown in FIG. 5. In FIG. 5, the ordinate indicates thetotal score of the von Frey test, and a higher value indicates astronger pain. As the vehicle of the test compound suspension, 0.5%methyl cellulose was used. The pharmacological effect was evaluated bystatistical analysis using the group of STZ administration+vehicleadministration as a control, by Wiiliams test for the Example2-B-administered group and by unpaired t-test for thepregabalin-administered group. The symbols “*” and “#” in the figureindicate statistical significance based on comparison with the group ofSTZ administration+vehicle administration (*: p<0.025, #: p<0.05).

Based on the results of the von Frey test obtained with the compound ofExample 2-B, the oral administration of 1 and 10 mg/kg of the compoundsignificantly improved the total score of the von Frey test. It wasrevealed from these test results that Compound (I) is effective for paindue to diabetic neuralgia.

Example 75 Human and Mouse Liver Microsomal Stability Assay

A liver microsomal stability assay, which is known to be an in vitroassay for evaluation of the stability of a compound against hepaticmetabolism, was carried out to evaluate the stability of Compound (I)against human and mouse hepatic metabolism.

A total of 4 times of experiments were carried out for the combinationsof the compound of Example 2-B or the compound of Comparative Example 29as the test compound and human liver microsomes (Xenotech) or mouseliver microsomes (Xenotech) as the liver microsomes.

The respective reagents to be used for the liver microsomal stabilityassay were prepared as follows. That is, an appropriate amount ofD-glucose 6-phosphate disodium salt (hereinafter referred to as G6P) wasdissolved in distilled water at 100 mmol/L, to prepare 100 mmol/Laqueous G6P solution. In 5 mL of distilled water, 1000 units of Glucose6-phosphate dehydrogenase from Yeast (hereinafter referred to as G6PDH)was dissolved, to prepare 200 units/mL aqueous G6PDH solution. Anappropriate amount of MgCl₂ was dissolved in distilled water at 100mmol/L, to prepare 100 mmol/L aqueous MgCl₂ solution. To 500 mL of 200mmol/L aqueous K₂HPO₄ solution, 200 mmol/L aqueous KH₂PO₄ solution(about 130 mL) was added, and pH was adjusted to 7.4, to prepare 200mmol/L KH₂PO₄/K₂HPO₄ buffer pH7.4 (hereinafter referred to as 200 mmol/LPB). β-nicotinamide-adenine dinucleotide phosphate, reduced form,tetrasodium salt (hereinafter referred to as (NADPH) was dissolved indistilled water such that the NADPH content becomes 10 mmol/L based onthe purity (Purity NADPH) in the assay data described in the attacheddocument, to prepare 10 mmol/L aqueous NADPH solution.

The liver microsomal stability assay was carried out according to thefollowing procedure. First, the reagents listed in Table 12 (excludingmicrosomes) were mixed together to prepare a reaction mixture, and thereaction mixture was aliquoted in 130 μL volumes to 4 wells (which playroles as the wells for the O-minute reaction, well for the 30-minutereaction, well for the 20-minute reaction and well for the 10-minutereaction, respectively) in a 96-well tube plate (BM Equipment Co., Ltd;hereinafter referred to as plate). The entire plate was covered with asilicone cap, and the plate was subjected to preincubation by beingsoaked in a water bath at 37° C. for 10 minutes.

After the preincubation, 3.75 μL of 20 mg/mL microsome suspension +16.25μl of distilled water (20 μL in total) were added to the well for the30-minute reaction, and the plate was covered with the cap, followed bysoaking the plate in a water bath at 37° C. to initiate the reaction.

Ten minutes after the beginning of the reaction, 3.75 μL of 20 mg/mLmicrosome suspension +16.25 μL of distilled water (20 μL in total) wereadded to the well for the 20-minute reaction, and 20 minutes after thebeginning of the reaction, 3.75 μL of 20 mg/mL microsome suspension+16.25 μL of distilled water (20 μL in total) were added to the well forthe 10-minute reaction. The reaction was further continued by keepingthe plate soaked in the water bath at 37° C.

Thirty minutes after the beginning of the reaction, the plate wasremoved from the water bath, and 120 μL of acetonitrile was added toeach well, followed by covering the plate with the cap, stirring theplate for 10 seconds with Direct Mixer, and stopping the reaction by 10minutes of ice cooling. After the reaction was stopped, 3.75 μL of 20mg/mL microsome suspension +16.25 μL of distilled water (20 μL in total)were added to the well for the O-minute reaction.

TABLE 12 Amount to be added (μL) Final concentration   10 mmol/L NADPH15.0  1 mmol/L  100 mmol/L G6P 15.0  10 mmol/L  200 units/mL G6PDH 0.75 1 unit/mL  100 mmol/L MgCl₂ 12.0  8 mmol/L  200 mmol/L PB 75.0 100mmol/L 0.05 mmol/L Test compound 6.0  2 μmol/L Distilled water 6.25Microsomes (20 mg/mL) 3.75  0.5 mg/mL Distilled water 16.25 Total amount150.0 —

The reaction liquid in each well was centrifuged at 4° C. at 2500 rpmfor 10 minutes, and the supernatant was transferred to a glass-coatedmicroplate (TOMSIC Plate+) to begin LC/MS/MS analysis. The conditionsfor the LC/MS/MS analysis were as follows:

HPLC system: NANOSPACE SI-2 (Shiseido)

Column: CAPCELLPAK MG S-5 2.0 mm

-   -   ID×50 mm C18 (Shiseido)

Mobile phase: 0.1% Formic acid/Acetonitrile

Flow rate: 0.4 mL/min

Gradient program: 30→80B %, 0.5 to 5 min. (Linear)

MS/MS system: API-5000 (Applied Biosystems).

For the chromatogram of the reaction liquid in each well obtained by theLC/MS/MS analysis, the peak area of the test compound was confirmed, andtest compound remaining rate (%) at each reaction time t (min.) wascalculated taking the peak area at the reaction time of 0 minute as100%. The test compound remaining rate was semi-logarithmically plottedagainst the reaction time and fitted to Equation 1 by the least squaresmethod, thereby calculating the elimination rate constant k (1/min.).Further, the obtained k was divided by the microsome proteinconcentration, to calculate hepatic intrinsic clearance CL_(int)(mL/min./mg) (Equation 2).

Substrate remaining rate=A×exp(−kt).  Equation 1

CL _(int)=k/microsome protein concentration  Equation 2

The values of the hepatic intrinsic clearance obtained as a result ofthe total of 4 times of the liver microsomal stability assay are shownin Table 13 and Table 14. A higher hepatic intrinsic clearance indicatesfaster metabolism of the compound in liver microsomes.

TABLE 13 Hepatic intrinsic clearance (mL/min./mg) Test compound MouseHuman Example 2-B 0.0168 0.0148 Comparative Example 29 0.267 0.110

As shown in Table 13, the hepatic intrinsic clearance obtained by theliver microsomal stability assay using the compound of Example 2-B asthe test compound was extremely smaller than that using the compound ofComparative Example 29 as the test compound. From these test results, itwas revealed that Compound (I) having a cyclohexane skeleton remarkablyimproves the metabolic stability in liver.

Table 14 shows the results of the human liver microsomal stabilityassay. When compared with Comparative Example 29 in Table 13, Examples2-A, 4-B, 28, 30, 33, 35, 59, 62, 64 and 67-B showed smaller humanhepatic intrinsic clearance, indicating that the metabolic stability inliver was improved.

TABLE 14 Human hepatic Human hepatic intrinsic clearance intrinsicclearance Test Compound (mL/min/mg) Test compound (mL/min/mg) Example2-A 0.0451 Example 4-B 0.00869 Example 28 0.00319 Example 30 0.00392Example 33 0.0580 Example 35 0.0250 Example 59 0.0446 Example 62 0.0333Example 64 0.00206 Example 67-B 0.0127

Example 76 Pharmacokinetics (PK) Test

Example 2-B or Comparative Example 29 was orally administered to mice,and the plasma level after the administration was measured to study theinfluence of improvement of the metabolic stability in liver microsomeson the change in the plasma level of the compound.

Female CD1 (ICR) mice of 7 weeks old which had been fed ad libitum withpellets (Oriental Yeast Co., Ltd.) and tap water were fasted for 17hours before the administration. Feeding to the mice was begun again 4hours after the administration.

The compound of Example 2-B was dissolved in DMSO:Tween 80:distilledwater (1:1:8), or the compound of Comparative Example 29 was dissolvedin 27% aqueous HP-β-CD solution, to prepare each solution to beadministered that contained the compound at a concentration of 0.2mg/mL.

In the case of intravenous administration of the solution, the animalwas fixed in a holder, and the administration was carried out from thetail vein without anesthesia, using a syringe with an injection needle(25 G) attached thereto. In the case of oral administration, a syringewith a feeding needle attached thereto was used without anesthesia toforce the solution into the stomach.

In terms of the mice to which the solution was intravenouslyadministered, blood was collected a total of 8 times from the jugularvein or heart 5, 15 and 30 minutes and 1, 2, 4, 8 and 24 hours after theintravenous administration. In terms of the mice to which the solutionwas orally administered, blood was collected a total of 8 times from thejugular vein or heart 15, 30 and 45 minutes and 1, 2, 4, 8 and 24 hoursafter the oral administration. Further, from the jugular vein or heartof mice to which the solution was not administered, blood was collectedas a blank. The collected blood was centrifuged at 4° C. at 12000 rpmfor 5 minutes, and the obtained mouse plasma and blank plasma werestored at about −20° C. until preparation of samples for analysis.

To 50 μL of a mouse plasma sample, or a mouse plasma sampleappropriately diluted with the blank plasma, an internal standardsolution and 150 μL of methanol were added, and the resulting mixturewas stirred, followed by cooling the mixture at 4° C. for 20 minutes. Interms of calibration curve samples, blank plasma to which a standardsolution for a calibration curve was added was prepared by the sameprocess. Each sample after the cooling was centrifuged (Hitachi KokiCo., Ltd.) at 4° C. at 2000 rpm for 10 minutes, and the supernatant wastransferred onto a 0.20 μM filter plate (Whatman), followed bycentrifugal filtration (Hitachi Koki Co., Ltd.) at 4° C. at 2000 rpm for10 minutes. The obtained filtrate was subjected to LC/MS/MS analysis.The conditions for the LC/MS/MS analysis were the same as those in theabove-described human and mouse liver microsomal stability assay.

From the results of the LC/MS/MS analysis, a calibration curve wasprepared using Analysis 1.4 (Applied Biosystems). Based on the LC/MS/MSanalysis and the prepared calibration curve, the concentration in eachmeasurement sample was calculated using Analysis 1.4. For 3 times eachof the experiments by intravenous administration and oraladministration, the mean plasma level at each time point was calculated,and PK analysis was carried out using the obtained values (FIG. 6 andFIG. 7; each plot indicates the mean plasma level at each time point andits ± standard deviation; i.v. indicates test data by intravenousadministration; and p.o. indicates test data by oral administration).The PK parameter was calculated using WinNonlin (Pharsight) by analysisindependent of the models (intravenous administration: Model 201, oraladministration: Model 200). Further, the bioavailability (BA) wascalculated by normalization by dividing AUC_(0-24 hr) from the timepoint of the intravenous administration or oral administration to thetime point of the final blood collection by the dose.

As shown in FIG. 6 and FIG. 7, the mean plasma level in the mice towhich the compound of Example 2-B was administered was higher than themean plasma level in the mice to which the compound of ComparativeExample 29 was administered, at all the time points. Further, BA, whichindicates the ratio of oral absorption, was 88% for the compound ofExample 2-B, but it was as low as 54% for the compound of ComparativeExample 29. Further, the total body clearance, which indicates the rateof disappearance of a compound, was 971 mL/hr/kg for the compound ofExample 2-B, but it was as high as 5672 mL/hr/kg for the compound ofComparative Example 29. From these test results, it was revealed thatCompound (I) having a cyclohexane skeleton remarkably improves themetabolic stability compared to similar compounds having no cyclohexaneskeleton.

Example 77 Evaluation of Safety Using Mice 1. Experimental Method

Crlj:CD1 (ICR) mice of 7 weeks old were subjected to repeated oraladministration of Example 2-B or Comparative Example 29 for 5 days, andobservation of clinical sign, measurement of body weight, hematology,blood chemistry, gross autopsy, measurement of organ weight andhistopathology were carried out. Further, on Day 1 and Day 5 after theadministration, TK measurement was carried out. Exposure to therespective compounds was confirmed.

The doses of Example 2-B were 0, 40, 200 and 1000 mg/kg/day, and thoseof Comparative Example 29 were 0, 30, 100 and 300 mg/kg/day. Thesolution to be administered was prepared using 0.5% aqueous methylcellulose solution as a vehicle, such that the administration volumebecomes 10 mL/kg.

2. Results

In the animals to which Example 2-B was administered, possibilities ofinduction of hepatotoxicity, effects on immune organs/tissues andinduction of gastrointestinal toxicity were suggested at 1000 mg/kg/day,and the no-observed-adverse-effect-level was assumed to be 200mg/kg/day.

On the other hand, in the animals to which Comparative Example 29 wasadministered, possibilities of induction of hepatotoxicity anddrug-induced phospholipidosis were suggested at not less than 30mg/kg/day, and the no-observed-adverse-effect-level was assumed to beless than 30 mg/kg/day. From these results, cyclohexane derivatives (I)represented by Example 2-B can be expected to be superior to thecompound described in WO 08/105,383, in view of safety.

Example 78

Prodrugs of Example 2-B were synthesized.

4-Hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-cyclohexyldimethylcarbamate (78-A)

A solution of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexane-cis-1,4-diol(Example 2-B) (230 mg, 0.60 mmol) in tetrahydrofuran (6.0 ml) wasstirred on ice for 10 minutes. To the reaction liquid, sodium hydride(26.4 mg, 0.66 mmol) was added, and the resulting mixture was stirred atthe same temperature for 20 minutes, followed by addingdimethylcarbamoyl chloride (84 μl, 0.9 mmol) dropwise thereto. Theresulting mixture was stirred at room temperature for 3 hours, and brinewas added to the reaction liquid, followed by extraction with ethylacetate. The organic layer was washed with brine and dried overanhydrous sodium sulfate, followed by concentration under reducedpressure. The residue was purified by flash column chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(95.6 mg, 0.21 mmol, 35%) as a pale yellow amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.93-2.04 (8H, m), 2.33 (3H, s), 2.71 (1H,s), 2.92 (6H, s), 3.80 (3H, s), 4.73-4.79 (1H, m), 6.37 (1H, s), 6.84(2H, d, J=8.8 Hz), 7.09-7.09 (4H, m), 7.20 (2H, J=8.8 Hz).

ESI-MS: m/z=450 (M+H)⁺

Cyclohexyl4-hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-cyclohexylcarbonate (78-B)

A solution of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexane-cis-1,4-diol(Example 2-B) (250 mg, 0.66 mmol) in tetrahydrofuran (2.2 ml) was cooledon ice, and sodium hydride (63.4 mg, 1.45 mmol) was added thereto,followed by stirring the resulting mixture at the same temperature for10 minutes. Cyclohexyl 1-iodoethyl carbonate (354 mg, 1.18 mmol) wasthen added to the mixture, and the resulting mixture was stirred at roomtemperature for 12 hours. To the reaction liquid, brine was added, andthe resulting mixture was extracted with ethyl acetate. The organiclayer was washed with brine and dried over anhydrous sodium sulfate,followed by concentration under reduced pressure. The residue waspurified by flash column chromatography (silica gel, n-hexane/ethylacetate) to obtain the captioned compound (161 mg, 0.29 mmol, 44%) as awhite amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.23-1.28 (4H, m), 1.31-1.40 (2H, m),1.44-1.56 (4H, m), 1.70-1.79 (4H, m), 1.93-2.08 (4H, m), 2.32 (3H, s),2.82 (1H, s), 3.79 (3H, s), 4.57-4.64 (1H, m), 4.67-4.71 (1H, m), 6.38(1H, s), 6.84 (2H, d, J=8.4 Hz), 7.08-7.08 (4H, m), 7.19 (2H, J=8.4 Hz).

ESI-MS: m/z=505 (M+H)⁺

By the same procedure as described above, the following compounds wereprepared.

TABLE 15-1 Example Structural Formula Compound Data 78-C

¹H-NMR (400 MHz, CDCl3) δ: 1.32 (3H, t, J = 8.0 Hz), 1.97-2.09 (8H, m),2.33 (3H, s), 2.62 (1H, s), 3.80 (3H, s), 4.20 (2H, q, J = 8.0 Hz),4.69-4.71 (1H, m), 6.37 (1H, s), 6.84 (2H, d, J = 8.8 Hz), 7.09-7.09(4H, m), 7.20 (2H, J = 8.8 Hz). ESI-MS: m/z = 451 (M + H)⁺ 78-D

¹H-NMR (400 MHz, CDCl₃) δ: 1.21 (9H, s), 1.92-2.06 (9H, m), 2.33 (3H,s), 3.80 (3H, s), 4.80-4.86 (1H, m), 6.38 (1H, s), 6.84 (2H, d, J = 8.4Hz), 7.09-7.09 (4H, m), 7.20 (2H, J = 8.4 Hz). ESI-MS: m/z = 463 (M +H)⁺

Succinic acidmono-4-hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-cyclohexylester (78-E)

To a solution of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexane-cis-1,4-diol(Example 2-B) (250 mg, 0.66 mmol) in DMF (3.3 ml), sodium hydride (63.4mg, 1.45 mmol) was added, and the resulting mixture was stirred for 30minutes. Succinic anhydride (99 mg, 0.99 mmol) was then added thereto,and the resulting mixture was stirred for 12 hours, followed by adding 1M-hydrochloric acid and ethyl acetate to the reaction liquid andextraction with ethyl acetate. The organic layer was washed with brineand dried over anhydrous sodium sulfate, followed by concentration underreduced pressure. The residue was purified by flash columnchromatography (silica gel, n-hexane/ethyl acetate) to obtain thecaptioned compound (87.0 mg, 0.18 mmol, 28%) as a white amorphousproduct.

¹H-NMR (400 MHz, CDCl₃) δ: 1.86-1.88 (2H, m), 1.96-2.02 (4H, m),2.08-2.11 (3H, m), 2.32 (3H, s), 2.58-2.64 (4H, m), 3.81 (3H, s),4.82-4.88 (1H, m), 6.38 (1H, s), 6.84 (2H, d, J=8.0 Hz), 7.09-7.09 (4H,m), 7.18 (2H, J=8.0 Hz).

ESI-MS: m/z=479 (M+H)⁺

Cyclohexyl(4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyloxy)ethylcarbonate (78-F)

To a solution of1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexane-cis-1,4-diol(Example 2-B) (400 mg, 1.05 mmol) in dichloroethane (5.4 ml), cyclohexyl1-iodoethyl carbonate (567 mg, 1.90 mmol), diisopropylethylamine (460μl, 2.64 mmol) and silver chloride (273 mg, 1.90 mmol) were added, andthe resulting mixture was stirred at 80° C. for 12 hours, followed byallowing the mixture to cool to room temperature and filtering thereaction liquid through Celite. To the filtrate, 1 M-hydrochloric acidand ethyl acetate were added, and the resulting mixture was extractedwith ethyl acetate. The organic layer was washed with brine and driedover anhydrous sodium sulfate, followed by concentration under reducedpressure. The residue was purified by flash column chromatography(silica gel, n-hexane/ethyl acetate) to obtain the captioned compound(31.9 mg, 0.058 mmol, 5.1%) as a white amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.15-1.34 (9H, m), 1.48-1.65 (4H, m),1.83-1.98 (8H, m), 2.33 (3H, s), 2.49 (1H, s), 3.52-3.58 (1H, m),3.64-3.71 (1H, m), 3.81 (3H, s), 4.92 (1H, q, J=5.2 Hz), 6.39 (1H, s),6.84 (2H, d, J=8.8 Hz), 7.09-7.09 (4H, m), 7.19 (2H, J=8.8 Hz).

ESI-MS: m/z=549 (M+H)⁺

By the same procedure as described above, the following compounds wereprepared.

TABLE 15-2 Example Structural Formula Compound Data 78-G

¹H-NMR (400 MHz, CDCl₃) δ: 1.26 (3H, t, J = 5.0 Hz), 1.33 (3H, d, J =4.8 Hz), 1.86-2.01 (8H, m), 2.33 (3H, s), 2.49 (1H, s), 3.49-3.53 (1H,m), 3.65-3.70 (2H, m), 3.80 (3H, s), 4.84 (1H, q, J = 4.8 Hz), 6.39 (1H,s), 6.84 (2H, d, J = 8.0 Hz), 7.09-7.09 (4H, m), 7.19 (2H, J = 8.0 Hz).ESI-MS: m/z = 495 (M + H)⁺ 78-H

¹H-NMR (400 MHz, CDCl₃) δ: 1.23 (9H, s), 1.89-2.00 (6H, m), 2.05-2.08(2H, m),2.33 (3H, s), 2.48 (1H, s), 3.67-3.71 (1H, m), 3.81 (3H, s),5.39 (2H, s), 6.38 (1H, s), 6.84 (2H, d, J = 9.2 Hz), 7.09-7.09 (4H, m),7.19 (2H, J = 9.2 Hz). ESI-MS: m/z = 493 (M + H)⁺

4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyl2-aminoacetate

To a solution of4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyl2-benzyloxycarbonylaminoacetate (Reference Example 97) (33.2 mg, 0.058mmol) in methanol (2.00 mL), 10% palladium/carbon (6.16 mg, 50 wt %) wasadded at room temperature, and the resulting mixture was stirred for 14hours under hydrogen atmosphere. The reaction liquid was filteredthrough Celite, and the filtrate was concentrated under reducedpressure. The residue was purified by flash column chromatography (NHsilica gel, chloroform/methanol) to obtain the captioned compound (18.4mg, 0.042 mmol, 73%) as a colorless amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 1.58-1.82 (2H, m), 1.88-2.12 (9H, m), 2.33(3H, s), 3.43 (2H, s), 3.81 (3H, s), 4.88-4.94 (1H, m), 6.37 (1H, s),6.83-6.87 (2H, m), 7.09-7.11 (4H, m), 7.18-7.22 (2H, m).

ESI-MS: m/z=436 (M+H)⁺

By the same procedure as described above, the following compound wasprepared.

TABLE 15-3 Example Structural Formula Compound Data 78-J

¹H-NMR (400 MHz, CDCl₃) δ: 0.93 (3H, d, J = 6.4 Hz), 1.00 (3H, d, J =6.4 Hz), 1.90-2.10 (9H, m), 234 (3H, s), 3.31 (1H, d, J = 8.0 Hz), 3.81(3H, s), 4.88-4.94 (1H, s), 6.36, (1H, s), 6.83-6.87 (2H, m), 7.09-7.11(4H, m), 7.18-7.22 (2H, m). ESI-MS: m/z = 460 (M − OH)⁺

(S)-4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyl2-amino-3-methylbutanoate (78-K)

To a mixed solution of(S)-4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyl2-benzyloxycarbonylamino-3-methylbutanoate (Reference Example 99) (122mg, 0.190 mmol) in dioxane/ethanol (2.00 mL/2.00 mL), 2,2′-bipyridyl(15.0 mg, 0.096 mmol) and 10% palladium/carbon (49.0 mg, 40 wt %) wasadded at room temperature, and the resulting mixture was stirred for 14hours under hydrogen atmosphere. The reaction liquid was filteredthrough Celite, and the filtrate was concentrated under reducedpressure. The residue was purified by flash column chromatography(silica gel, chloroform/methanol) to obtain the captioned compound (38.6mg, 0.076 mmol, 40%) as a colorless amorphous product.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (3H, d, J=6.8 Hz), 1.02 (3H, d, J=6.8Hz), 1.90-2.12 (9H, m), 2.34 (3H, s), 3.32-3.34 (1H, m), 3.67-3.76 (1H,m), 3.81 (3H, s), 5.41 (1H, d, J=6.4 Hz), 5.47 (1H, d, J=6.4 Hz), 6.38,(1H, s), 6.83-6.87 (2H, m), 7.09-7.12 (4H, m), 7.18-7.22 (2H, m).

ESI-MS: m/z=490 (M−OH)⁺

4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyldihydrogen phosphate (78-L)

To a mixed solution of dibenzyl4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexylphosphate (Reference Example 100) (251 mg, 0.393 mmol), methanol (2.6mL) and ethyl acetate (2.6 mL), 10% palladium/carbon (41.8 mg, 50 wt %)was added, and the resulting mixture was stirred under hydrogenatmosphere at room temperature for 2.5 hours. The reaction liquid wasfiltered through Celite, and the filtrate was concentrated under reducedpressure. The residue was recrystallized from dichloromethane/diethylether to obtain the captioned compound (97.2 mg, 0.212 mmol, 54%) as awhite solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.68-1.98 (8H, m), 2.28 (3H, s), 3.76 (3H,s), 4.13 (1H, br), 4.92 (1H, br), 6.53 (1H, s), 6.91-6.95 (2H, m),7.08-7.17 (6H, m).

ESI-MS: m/z=459 (M+H)⁺

INDUSTRIAL APPLICABILITY

The cyclohexane derivative or a pharmaceutically acceptable salt thereofor a prodrug thereof can exert an analgesic action against nociceptivepain, neuropathic pain and diabetic neuropathic pain, and has less sideeffects, so that it may be used as a pharmaceutical for a wide range ofpain symptoms.

1. A method for relieving pain, comprising administering an effectiveamount of a cyclohexane derivative represented by Formula (I):

wherein A represents a substituent represented by Formula (IIa) or(IIb):

R¹ and R² each independently represent a hydrogen atom, chlorine atom,C₁-C₃ haloalkyl, C₁-C₄ alkyl, C₁-C₄ alkoxy or cyano; R³ represents ahydrogen atom or chlorine atom; R⁴ represents a fluorine atom,hydroxymethyl or hydroxyl; R⁵ and R⁶ each independently represent ahydrogen atom, fluorine atom, C₁-C₃ haloalkyl, carboxyl,methoxycarbonyl, ethoxycarbonyl, C₁-C₄ alkoxy, hydroxyl or C₂-C₅alkylcarbonyloxy, or R⁵ and R⁶ may together form an oxo group; R⁷ and R⁸each independently represent a hydrogen atom or fluorine atom; Yrepresents an oxygen atom or sulfur atom; and Z represents a nitrogenatom or methane or a pharmaceutically acceptable salt thereof or aprodrug thereof.
 2. The method according to claim 1, wherein the pain isneuropathic pain and/or nociceptive pain.
 3. The method according toclaim 1, wherein the pain is diabetic neuropathic pain.
 4. A method forrelieving pain, comprising administering an effective amount of thecyclohexane derivative represented by Formula (I):

wherein A represents a substituent represented by Formula (IIc) or(IId):

R¹ and R² each independently represent a hydrogen atom, chlorine atom,C₁-C₃ haloalkyl, C₁-C₄ alkyl or C₁-C₄ alkoxy; R³ represents a hydrogenatom or chlorine atom; R⁴ represents a fluorine atom, hydroxymethyl orhydroxyl; R⁵ and R⁶ each independently represent a hydrogen atom,fluorine atom, C₁-C₃ haloalkyl, carboxyl, alkoxy, hydroxyl or C₂-C₅alkylcarbonyloxy, or R⁵ and R⁶ may together form an oxo group; Yrepresents an oxygen atom or sulfur atom; and Z represents a nitrogenatom or methane or a pharmaceutically acceptable salt thereof or aprodrug thereof.
 5. The method according to claim 4, wherein the pain isneuropathic pain and/or nociceptive pain.
 6. The method according toclaim 4, wherein the pain is diabetic neuropathic pain.